JP7047772B2 - Brk inhibitor compound - Google Patents

Description

（式中、全ての記号は後記と同じ意味を表す。）で示される、Ｂｒｋ阻害化合物、その塩、そのＮ－オキシド体、その溶媒和物、またはそれらのプロドラッグ（以下、本発明化合物という。）、およびそれらを有効成分として含有する医薬に関する。The present invention relates to Brk inhibitor compounds, salts thereof, N-oxides thereof, solvates thereof, or prodrugs thereof, and pharmaceuticals containing them as active ingredients. For details, see the general formula (I).

(In the formula, all symbols have the same meanings as described below.) A Brk inhibitor compound, a salt thereof, an N-oxide form thereof, a solvate thereof, or a prodrug thereof (hereinafter referred to as a compound of the present invention). ), And pharmaceuticals containing them as active ingredients.

Brk (Breast tumor kinase), also referred to as PTK6 (protein tyrosine kinase 6), is a non-receptor tyrosine kinase belonging to the FRK (Finn-related kinase) / PTK6 family kinase, which is a tyrosine kinase. Brk is encoded by 451 amino acids. Brk was first identified in normal human melanocytes and shortly thereafter in breast cancer. Brk is breast cancer, ovarian cancer, colon cancer, pancreatic cancer, bladder cancer, esophageal cancer, gastric cancer, non-small cell lung cancer, prostate cancer, oral squamous epithelial cancer, head and neck squamous epithelial cancer, melanoma. , B-cell lymphoma, and many tumors, including T-cell lymphoma. In particular, in breast cancer, prostate cancer, nasopharyngeal cancer, and non-small cell lung cancer, Brk is a poor prognostic factor. In addition, Brk is considered to play an important role in tumorigenesis such as promoting cancer cell proliferation, migration, and infiltration, and avoiding cell death (see Non-Patent Document 1-7). ).

Therefore, compounds that inhibit the activation of Brk are considered to be useful in the treatment of various cancers.

On the other hand, Patent Document 1 describes a compound of the following formula (IA) or a compound of the following formula (IA) for the treatment of diseases related to Syk and / or JAK, such as heart disease, inflammatory disease, immune-related disease, and cell proliferation disorder. It is described that the homozygous forms, or pharmaceutically acceptable salts thereof, are used.

（式中、
Ｙ^1Aは、Ｎ、ＣＨ、およびＣからなる群から選択され；
Ｚ^1Aは、結合、－Ｎ（Ｃ１－４アルキル）－、－ＳＯ₂－、および－ＣＯ－などからなる群から選択され；
Ｒ^1Aは、水素および置換基で置換されていてもよいＣ１－８アルキルなどから選択され；
Ｒ^2Aは、水素およびＣ１－８アルキルなどから選択され；
Ｒ^3Aは、水素およびＣ１－８アルキルなどから選択され；
Ｒ^4Aは、Ｃ１－８アルコキシ、アミノ、Ｃ１－８アルキルカルボニル、およびアミノカルボニルＣ１－８アルコキシから各々独立に選択される１～３の置換基で置換されていてもよいアリールなどから選択され；
Ｒ^4’Aは、水素およびＣ１－８アルキルなどから選択され；
Ｒ^5Aは、水素、Ｃ１－８アルキル、およびＣ３－８シクロアルキルなどから選択され；
Ｒ^6Aは、水素、Ｃ１－８アルキル、ハロ、ヒドロキシル、およびオキソからなる群から選択され；
Ｒ^7Aは、水素、Ｃ１－８アルキル、ハロおよびアリールなどからなる群から選択され、アリールおよびヘテロアリールは各々、ハロ、Ｃ１－８アルキル、Ｃ１－８アルコキシ、シアノ、アミノ、ヒドロキシル、ヘテロアリールで置換されていてもよく；
および破線は二重結合または単結合を示す。（基の定義を一部抜粋した。））である。The general formula (IA) is

(During the ceremony,
Y ^1A is selected from the group consisting of N, CH, and C;
Z ^1A is selected from the group consisting of bonds, -N (C1-4alkyl)-, -SO _2- ,, -CO-, and the like;
R ^1A is selected from hydrogen and C1-8 alkyl which may be substituted with substituents, etc .;
R ^2A is selected from hydrogen and C1-8 alkyl and the like;
R ^3A is selected from hydrogen and C1-8 alkyl and the like;
R ^4A is selected from aryls and the like, which may be substituted with 1-3 substituents independently selected from C1-8 alkoxy, amino, C1-8 alkylcarbonyl, and aminocarbonyl C1-8 alkoxy, respectively;
R ^4'A is selected from hydrogen and C1-8 alkyl and the like;
R ^5A is selected from hydrogen, C1-8 alkyl, C3-8 cycloalkyl and the like;
R ^6A is selected from the group consisting of hydrogen, C1-8 alkyl, halo, hydroxyl, and oxo;
R ^7A is selected from the group consisting of hydrogen, C1-8 alkyl, halo and aryl, etc., and aryl and heteroaryl are halo, C1-8 alkyl, C1-8 alkoxy, cyano, amino, hydroxyl, heteroaryl, respectively. May be replaced;
And dashed lines indicate double or single bonds. (A part of the definition of the group is excerpted.)).

Further, Patent Document 2 describes that the compound of the following formula (IB) is a Toll Like Receptor agonist, and these compounds are used for the treatment of autoimmune diseases, cancer and the like. Has been done.

（式中、
Ｘ^Bは窒素またはＣＲ^8Bであり；
破線は任意の二重結合であり；

が二重結合であるとき、Ｑ^1Bは酸素または硫黄などであり；
Ｚ^Bは酸素、硫黄、またはＮＹ^5Bであり、Ｙ^5Bは水素またはアルキルなどであり；
Ｑ^2Bは置換されたまたは無置換のアリールもしくはヘテロアリールなどであり；
Ｑ^4Bは水素などであり；
Ｒ^2Bは水素、アルキル、またはＮＹ^6BＹ^7Bであり、Ｙ^6BおよびＹ^7Bは、それぞれ独立して、水素、置換されたまたは無置換のアリールもしくはヘテロアリールなどである。（基の定義を一部抜粋した。））である。The general formula (IB) is

(During the ceremony,
X ^B is nitrogen or CR ^8B ;
The dashed line is any double bond;

When is a double bond, Q ^1B is oxygen or sulfur, etc .;
Z ^B is oxygen, sulfur, or NY ^5B , Y ^5B is hydrogen or alkyl, etc;
Q ^2B is a substituted or unsubstituted aryl or heteroaryl, etc.;
Q ^4B is hydrogen etc .;
R ^2B is hydrogen, alkyl, or NY ^6B Y ^7B , and Y ^6B and Y ^7B are each independently hydrogen, substituted or unsubstituted aryl or heteroaryl, and the like. (A part of the definition of the group is excerpted.)).

Further, Patent Document 3 describes that the compound of the following formula (IC) is a p38 inhibitor, and these compounds are used for the treatment of autoimmune diseases, inflammatory diseases and the like.

（式中、
Ｖ^Cは、酸素または硫黄であり；
Ｘ^C、Ｗ^C、およびＺ^Cは、それぞれ独立して、Ｃ（Ｒ^4C）および窒素であり、ただし、Ｘ^C、Ｙ^C、およびＺ^Cのうち少なくとも１つは窒素であり；
Ｙ^Cは、結合、－Ｏ－、または－ＮＨ－などであり；
Ｒ^1Cは、置換されていてもよいアリールまたはヘテロアリールなどであり；
Ｒ^2Cは、水素、アシル、アルキル、またはヘテロシクロアルキルなどであり；
Ｒ^4Cは、水素、アシル、アルキル、アルキルアミノ、またはアミノなどであり；
Ｐ^Cは、置換されていてもよいアリール、ヘテロアリール、またはヘテロシクロアルキルであり；
Ｇ^1CおよびＧ^2Cは、それぞれ独立して、結合、アルキレン、－Ｃ（Ｏ）－、または－ＳＯ₂－などであり；
Ｇ^3Cは、水素またはアルキルなどである。（基の定義を一部抜粋した。））である。The general formula (IC) is

(During the ceremony,
^VC is oxygen or sulfur;
X ^C , W ^C , and Z ^C are independently C (R ^4C ) and nitrogen, except that at least one of X ^C , Y ^C , and Z ^C is nitrogen;
Y ^C is a bond, -O-, or -NH-, etc .;
R ^1C is an aryl or heteroaryl which may be substituted;
R ^2C can be hydrogen, acyl, alkyl, or heterocycloalkyl, etc .;
R ^4C can be hydrogen, acyl, alkyl, alkylamino, or amino;
PCs are ^aryls , heteroaryls, or heterocycloalkyls that may be substituted;
G ^1C and G ^2C are independently bonded, alkylene, -C (O)-, or -SO _2- , etc .;
G ^3C is hydrogen or alkyl and the like. (A part of the definition of the group is excerpted.)).

International Publication No. 2009/131678 Pamphlet International Publication No. 2007/142755 Pamphlet International Publication No. 2007/015877 Pamphlet

Breast Cancer-Current and Alternative Therapeutic Modalities, pp. 413-434, 2011 Biochimica et Biophysica Acta, Vol. 1806, pp. 66-73, 2010 Cell Cycle, Volume 8, pp. 2728-2732, 2009 Cancer Research, Vol. 73, pp. 5810-5820, 2013 Cancer Research, Vol. 73, pp. 5426-5437, 2013 OncoTargets and Therapy, Volume 6, pp. 183-188, 2013 Journal of Translational Medicine, Vol. 11, 59, 2013

An object of the present invention is to create a compound having an inhibitory activity against Brk, and to find a compound useful as a therapeutic agent for Brk-related diseases, particularly various cancer diseases.

As a result of diligent research to find a compound having an inhibitory activity against Brk in order to solve the above-mentioned problems, the present inventors have found a compound represented by the general formula (I) described later and completed the present invention.

（式中、
ｒｉｎｇ１およびｒｉｎｇ２は、それぞれ独立して、Ｃ５－１０炭素環または５－１０員複素環を表し、
Ｒ¹は、Ｃ１－４アルキル、Ｃ２－４アルケニル、Ｃ２－４アルキニル、Ｃ３－６シクロアルキル、または３－６員ヘテロシクロアルキルを表し、該Ｃ１－４アルキル、Ｃ２－４アルケニル、Ｃ２－４アルキニル、Ｃ３－６シクロアルキル、または３－６員ヘテロシクロアルキルは、１～５個のハロゲンまたは水酸基で置換されていてもよく、
Ｒ²は、ハロゲン、Ｃ１－４アルキル、ＯＲ⁴、ＮＲ⁵Ｒ⁶、またはオキソを表し、該Ｃ１－４アルキルは１～５個のハロゲンで置換されていてもよく、
Ｒ⁴は、水素原子、Ｃ１－４アルキル、またはベンゼン環を表し、該Ｃ１－４アルキルまたはベンゼン環は１～５個のハロゲンで置換されていてもよく、
Ｒ⁵およびＲ⁶は、それぞれ独立して、水素原子またはＣ１－４アルキルを表し、
Ｒ³は、ハロゲン、Ｃ１－４アルキル、ＯＲ⁷、ＮＲ⁸Ｒ⁹、ＳＯ₂Ｒ¹⁰、ＣＯＲ¹¹、ベンゼン環、４－６員複素環、またはオキソを表し、該Ｃ１－４アルキルは、ハロゲン、水酸基、４－６員複素環、およびＣＯＮＲ¹²Ｒ¹³からなる群より選択される、１～５個の置換基で置換されていてもよく、
Ｒ⁷は、水素原子またはＣ１－４アルキルを表し、該Ｃ１－４アルキルは、１～５個のハロゲンまたはＮＲ¹⁴Ｒ¹⁵で置換されていてもよく、
Ｒ⁸およびＲ⁹は、それぞれ独立して、水素原子、Ｃ１－４アルキル、またはアセチルを表し、
Ｒ¹⁰は、Ｃ１－４アルキルまたはＮＲ^１６Ｒ^１７を表し、
Ｒ¹¹は、水酸基、Ｃ１－４アルキル、ＮＲ^１８Ｒ^１９、または４－６員複素環を表し、該４－６員複素環は、ハロゲン、水酸基、およびＣ１－４アルキルからなる群より選択される、１～５個の置換基で置換されていてもよく、
Ｒ¹²、Ｒ¹³、Ｒ¹⁴、Ｒ¹⁵、Ｒ^１６およびＲ^１７は、それぞれ独立して、水素原子またはＣ１－４アルキルを表し、
Ｒ¹⁸およびＲ¹⁹は、それぞれ独立して、水素原子、Ｃ１－４アルキル、または４－６員複素環を表し、該Ｃ１－４アルキルは、１～５個の水酸基、Ｃ１－３アルコキシ、またはＮＲ^２０Ｒ^２１で置換されていてもよく、
Ｒ^２０およびＲ^２１は、それぞれ独立して、水素原子またはＣ１－４アルキルを表し、
ｐは、０～７の整数を表し、
ｑは、０～７の整数を表す。
ただし、ｐおよびｑがそれぞれ２以上の整数を表す場合、Ｒ²およびＲ³は、それぞれ独立して、同一でも異なっていてもよい。）
で示される化合物、その塩、そのＮ－オキシド体、その溶媒和物、またはそれらのプロドラッグ、
〔２〕 Ｒ¹が、１～５個のハロゲンまたは水酸基で置換されていてもよい、イソプロピル、ｔｅｒｔ－ブチル、イソブチル、Ｃ３－６シクロアルキル、または３－６員ヘテロシクロアルキルである前記〔１〕記載の化合物、その塩、そのＮ－オキシド体、その溶媒和物、またはそれらのプロドラッグ、
〔３〕 ｒｉｎｇ１が９－１０員含窒素二環式芳香族複素環である前記〔１〕または〔２〕記載の化合物、その塩、そのＮ－オキシド体、その溶媒和物、またはそれらのプロドラッグ、
〔４〕 ｒｉｎｇ２がベンゼン環である前記〔１〕乃至〔３〕のいずれかに記載の化合物、その塩、そのＮ－オキシド体、その溶媒和物、またはそれらのプロドラッグ、
〔５〕 ｑが１以上であって、Ｒ³が少なくとも１つはハロゲン、Ｃ１－３アルコキシ、ＳＯ₂Ｒ¹⁰、またはＣＯＲ¹¹である前記〔１〕乃至〔４〕のいずれかに記載の化合物、その塩、そのＮ－オキシド体、その溶媒和物、またはそれらのプロドラッグ、
〔６〕 一般式（Ｉ－１）

（式中、ｒｉｎｇ１－１はインドール環またはインダゾール環を表し、Ｒ^1-1はイソプロピル、ｔｅｒｔ－ブチル、シクロブチル、シクロペンチル、ジフルオロシクロペンチル、オキセタニル、またはテトラヒドロフラニルを表し、Ｘはハロゲンを表し、ｐ－１は０～６の整数を表し、ｑ－１は０～４の整数を表し、その他の記号は前記〔１〕記載の記号と同じ意味を表す。）
で示される前記〔１〕記載の化合物、その塩、そのＮ－オキシド体、その溶媒和物、またはそれらのプロドラッグ、
〔７〕 一般式（Ｉ－１’）

（式中、Ｒ^3’はＳＯ₂Ｒ¹⁰またはＣＯＲ¹¹を表し、その他の記号は前記〔１〕または〔６〕記載の記号と同じ意味を表す。）
で示される前記〔１〕記載の化合物、その塩、そのＮ－オキシド体、その溶媒和物、またはそれらのプロドラッグ、
〔８〕
（１） ６－アミノ－７－（７－フルオロ－１Ｈ－インダゾール－４－イル）－２－｛［２－フルオロ－４－（メチルスルホニル）フェニル］アミノ｝－９－イソプロピル－７，９－ジヒドロ－８Ｈ－プリン－８－オン、
（２） ６－アミノ－７－（７－クロロ－１Ｈ－インダゾール－４－イル）－２－｛［２－フルオロ－４－（メチルスルホニル）フェニル］アミノ｝－９－イソプロピル－７，９－ジヒドロ－８Ｈ－プリン－８－オン、
（３） ６－アミノ－７－（６，７－ジフルオロ－１Ｈ－インダゾール－４－イル）－２－｛［２－フルオロ－４－（メチルスルホニル）フェニル］アミノ｝－９－イソプロピル－７，９－ジヒドロ－８Ｈ－プリン－８－オン、
（４） ６－アミノ－７－（７－フルオロ－１Ｈ－インダゾール－４－イル）－２－｛［２－フルオロ－４－（メチルスルホニル）フェニル］アミノ｝－９－（２－メチル－２－プロパニル）－７，９－ジヒドロ－８Ｈ－プリン－８－オン、
（５） ２－［（４－アセチル－２－フルオロフェニル）アミノ］－６－アミノ－７－（１Ｈ－インダゾール－４－イル）－９－イソプロピル－７，９－ジヒドロ－８Ｈ－プリン－８－オン、
（６） ６－アミノ－９－シクロペンチル－２－｛［２－フルオロ－４－（メチルスルホニル）フェニル］アミノ｝－７－（１Ｈ－インダゾール－４－イル）－７，９－ジヒドロ－８Ｈ－プリン－８－オン、
（７） ６－アミノ－９－シクロブチル－２－｛［２－フルオロ－４－（メチルスルホニル）フェニル］アミノ｝－７－（１Ｈ－インダゾール－４－イル）－７，９－ジヒドロ－８Ｈ－プリン－８－オン、
（８） ６－アミノ－２－｛［２－フルオロ－４－（メチルスルホニル）フェニル］アミノ｝－７－（１Ｈ－インダゾール－４－イル）－９－（２－メチル－２－プロパニル）－７，９－ジヒドロ－８Ｈ－プリン－８－オン、
（９） ６－アミノ－２－｛［２－フルオロ－４－（メチルスルホニル）フェニル］アミノ｝－９－イソプロピル－７－（７－メチル－１Ｈ－インダゾール－４－イル）－７，９－ジヒドロ－８Ｈ－プリン－８－オン、
（１０） ６－アミノ－９－（３，３－ジフルオロシクロペンチル）－２－｛［２－フルオロ－４－（メチルスルホニル）フェニル］アミノ｝－７－（１Ｈ－インダゾール－４－イル）－７，９－ジヒドロ－８Ｈ－プリン－８－オン、
（１１） ６－アミノ－７－（７－クロロ－１Ｈ－インダゾール－４－イル）－９－イソプロピル－２－｛［２－メトキシ－４－（メチルスルホニル）フェニル］アミノ｝－７，９－ジヒドロ－８Ｈ－プリン－８－オン、
（１２） ６－アミノ－７－（７－フルオロ－１Ｈ－インダゾール－４－イル）－２－｛［２－メトキシ－４－（メチルスルホニル）フェニル］アミノ｝－９－（２－メチル－２－プロパニル）－７，９－ジヒドロ－８Ｈ－プリン－８－オン、
（１３） ６－アミノ－２－｛［２－フルオロ－４－（メチルスルホニル）フェニル］アミノ｝－７－（１Ｈ－インドール－６－イル）－９－（テトラヒドロ－３－フラニル）－７，９－ジヒドロ－８Ｈ－プリン－８－オン、
（１４） ６－アミノ－９－シクロペンチル－２－｛［２－フルオロ－４－（メチルスルホニル）フェニル］アミノ｝－７－（３－ヒドロキシフェニル）－７，９－ジヒドロ－８Ｈ－プリン－８－オン、
（１５） ６－アミノ－２－｛［２，３－ジフルオロ－４－（メチルスルホニル）フェニル］アミノ｝－７－（７－フルオロ－１Ｈ－インダゾール－４－イル）－９－イソプロピル－７，９－ジヒドロ－８Ｈ－プリン－８－オン、
（１６） ６－アミノ－２－｛［２，５－ジフルオロ－４－（メチルスルホニル）フェニル］アミノ｝－７－（７－フルオロ－１Ｈ－インダゾール－４－イル）－９－イソプロピル－７，９－ジヒドロ－８Ｈ－プリン－８－オン、
（１７） ６－アミノ－７－（３－アミノ－４－フルオロフェニル）－２－｛［２－フルオロ－４－（メチルスルホニル）フェニル］アミノ｝－９－イソプロピル－７，９－ジヒドロ－８Ｈ－プリン－８－オン、
（１８） ６－アミノ－７－（１－ベンゾフラン－５－イル）－２－｛［２－フルオロ－４－（メチルスルホニル）フェニル］アミノ｝－９－イソプロピル－７，９－ジヒドロ－８Ｈ－プリン－８－オン、
（１９） ６－アミノ－２－｛［２－フルオロ－４－（メチルスルホニル）フェニル］アミノ｝－７－（１Ｈ－インダゾール－４－イル）－９－（１，１，１－トリフルオロ－２－プロパニル）－７，９－ジヒドロ－８Ｈ－プリン－８－オン、
（２０） ６－アミノ－９－［（２Ｓ）－２－ブタニル］－７－（７－フルオロ－１Ｈ－インダゾール－４－イル）－２－｛［２－フルオロ－４－（メチルスルホニル）フェニル］アミノ｝－７，９－ジヒドロ－８Ｈ－プリン－８－オン、
（２１） ６－アミノ－７－（４－クロロ－３－ヒドロキシフェニル）－９－（３，３－ジフルオロシクロペンチル）－２－｛［２－フルオロ－４－（１－ピペラジニルカルボニル）フェニル］アミノ｝－７，９－ジヒドロ－８Ｈ－プリン－８－オン、
（２２） ６－アミノ－７－（１Ｈ－インドール－５－イル）－９－イソプロピル－２－［（２－メチル－１－オキソ－２，３－ジヒドロ－１Ｈ－イソインドール－５－イル）アミノ］－７，９－ジヒドロ－８Ｈ－プリン－８－オン、
（２３） ６－アミノ－２－［（１，３－ジメチル－１Ｈ－ピラゾール－４－イル）アミノ］－７－（１Ｈ－インドール－６－イル）－９－イソプロピル－７，９－ジヒドロ－８Ｈ－プリン－８－オン、
（２４） ４－｛［６－アミノ－７－（１Ｈ－インドール－５－イル）－９－イソプロピル－８－オキソ－８，９－ジヒドロ－７Ｈ－プリン－２－イル］アミノ｝－３－フルオロ－Ｎ，Ｎ－ジメチルベンズアミド、
（２５） ６－アミノ－９－シクロペンチル－７－（３－ヒドロキシフェニル）－２－（｛４－［２－（１－ピロリジニル）エチル］フェニル｝アミノ）－７，９－ジヒドロ－８Ｈ－プリン－８－オン、
（２６） ４－｛［６－アミノ－９－シクロペンチル－７－（３－ヒドロキシフェニル）－８－オキソ－８，９－ジヒドロ－７Ｈ－プリン－２－イル］アミノ｝－３－メトキシ－Ｎ，Ｎ－ジメチルベンズアミド、
（２７） ４－｛［６－アミノ－７－（４－クロロ－３－ヒドロキシフェニル）－９－イソプロピル－８－オキソ－８，９－ジヒドロ－７Ｈ－プリン－２－イル］アミノ｝－Ｎ－［２－（ジメチルアミノ）エチル］－３－フルオロベンズアミド、
（２８） ６－アミノ－９－シクロペンチル－２－｛［２－フルオロ－４－（４－モルホリニルカルボニル）フェニル］アミノ｝－７－（３－ヒドロキシフェニル）－７，９－ジヒドロ－８Ｈ－プリン－８－オン、
（２９） ４－｛［６－アミノ－９－シクロペンチル－７－（３－ヒドロキシフェニル）－８－オキソ－８，９－ジヒドロ－７Ｈ－プリン－２－イル］アミノ｝ベンズアミド、
（３０） ６－アミノ－９－シクロペンチル－７－（３－ヒドロキシフェニル）－２－｛［４－（４－モルホリニル）フェニル］アミノ｝－７，９－ジヒドロ－８Ｈ－プリン－８－オン、
（３１） ４－｛［６－アミノ－９－シクロペンチル－７－（３－ヒドロキシフェニル）－８－オキソ－８，９－ジヒドロ－７Ｈ－プリン－２－イル］アミノ｝－３－フルオロ－Ｎ－（２－ヒドロキシエチル）ベンズアミド、
（３２） ６－アミノ－２－（｛２－フルオロ－４－［（４－ヒドロキシ－１－ピぺリジニル）カルボニル］フェニル｝アミノ）－７－（１Ｈ－インドール－５－イル）－９－（テトラヒドロ－３－フラニル）－７，９－ジヒドロ－８Ｈ－プリン－８－オン、
（３３） ５－｛［６－アミノ－７－（１Ｈ－インドール－５－イル）－９－イソプロピル－８－オキソ－８，９－ジヒドロ－７Ｈ－プリン－２－イル］アミノ｝－Ｎ，Ｎ－ジメチル－２－ピリジンカルボキサミド、
（３４） ６－アミノ－７－（１Ｈ－インドール－５－イル）－９－イソプロピル－２－［（２－メチル－４－オキソ－４Ｈ－クロメン－７－イル）アミノ］－７，９－ジヒドロ－８Ｈ－プリン－８－オン、
（３５） ６－アミノ－７－（１Ｈ－インドール－５－イル）－９－イソプロピル－２－［（１－オキソ－１，３－ジヒドロ－２－ベンゾフラン－５－イル）アミノ］－７，９－ジヒドロ－８Ｈ－プリン－８－オン、
（３６） ７－｛［６－アミノ－７－（１Ｈ－インドール－５－イル）－９－イソプロピル－８－オキソ－８，９－ジヒドロ－７Ｈ－プリン－２－イル］アミノ｝－４－メチル－２Ｈ－１，４－ベンゾオキサジン－３（４Ｈ）－オン、または
（３７） ４－｛［６－アミノ－７－（１Ｈ－インドール－５－イル）－８－オキソ－９－（テトラヒドロ－３－フラニル）－８，９－ジヒドロ－７Ｈ－プリン－２－イル］アミノ｝－３－フルオロベンゼンスルホンアミド
である前記〔１〕記載の化合物、その塩、そのＮ－オキシド体、その溶媒和物、またはそれらのプロドラッグ、
〔９〕 前記〔１〕記載の一般式（Ｉ）で示される化合物、その塩、そのＮ－オキシド体、その溶媒和物、またはそれらのプロドラッグを有効成分として含有してなる医薬組成物、
〔１０〕 Ｂｒｋ阻害剤である前記〔９〕記載の組成物、
〔１１〕 がんの治療剤である前記〔９〕記載の組成物、
〔１２〕 がんが、乳がん、卵巣がん、大腸がん、肺がん、前立腺がん、頭頸部がん、リンパ腫、脳腫瘍、神経膠腫、下垂体腺腫、ぶどう膜悪性黒色腫、髄膜腫、胸腺腫、中皮腫、食道がん、胃がん、十二指腸がん、肝細胞がん、胆管がん、胆のうがん、膵臓がん、腎細胞がん、腎盂・尿管がん、膀胱がん、陰茎がん、精巣がん、子宮がん、膣がん、外陰がん、皮膚がん、悪性骨腫瘍、軟部肉腫、軟骨肉腫、白血病、骨髄異形成症候群、または多発性骨髄腫である前記〔１１〕記載の組成物、
〔１３〕 前記〔１〕記載の一般式（I）で示される化合物、その塩、そのＮ－オキシド体、その溶媒和物、またはそれらのプロドラッグを有効成分として含有するＢｒｋ関連疾患の予防および／または治療剤、
〔１４〕 Ｂｒｋ関連疾患ががんである前記〔１３〕記載の治療剤、
〔１５〕 がんが、乳がん、卵巣がん、大腸がん、肺がん、前立腺がん、頭頸部がん、リンパ腫、脳腫瘍、神経膠腫、下垂体腺腫、ぶどう膜悪性黒色腫、髄膜腫、胸腺腫、中皮腫、食道がん、胃がん、十二指腸がん、肝細胞がん、胆管がん、胆のうがん、膵臓がん、腎細胞がん、腎盂・尿管がん、膀胱がん、陰茎がん、精巣がん、子宮がん、膣がん、外陰がん、皮膚がん、悪性骨腫瘍、軟部肉腫、軟骨肉腫、白血病、骨髄異形成症候群、または多発性骨髄腫である前記〔１４〕記載の治療剤、
〔１６〕 前記〔１〕記載の一般式（Ｉ）で示される化合物、その塩、そのＮ－オキシド体、その溶媒和物、またはそれらのプロドラッグと、アルキル化剤、代謝拮抗剤、抗がん性抗生物質、植物性製剤、ホルモン剤、白金化合物、免疫調節剤、トポイソメラーゼ阻害剤、生物学的応答調節剤、キナーゼ阻害剤、免疫チェックポイント阻害剤、ヒストン脱アセチル化酵素（ＨＤＡＣ）阻害剤、プロテアソーム阻害剤、抗ＣＤ２０抗体、抗ＨＥＲ２抗体、抗ＥＧＦＲ抗体、および抗ＶＥＧＦ抗体から選ばれる少なくとも１種以上と組み合わせてなる医薬、
〔１７〕 前記〔１〕記載の一般式（Ｉ）で示される化合物、その塩、そのＮ－オキシド体、その溶媒和物、またはそれらのプロドラッグの有効量を、がんの治療を必要とする患者に投与することを特徴とする、がんの治療方法、
〔１８〕 がんの治療のための、前記〔１〕記載の一般式（Ｉ）で示される化合物、その塩、そのＮ－オキシド体、その溶媒和物、またはそれらのプロドラッグ、
〔１９〕 がんの治療剤を製造するための前記〔１〕記載の一般式（Ｉ）で示される化合物、その塩、そのＮ－オキシド体、その溶媒和物、またはそれらのプロドラッグの使用、および
〔２０〕 前記〔１〕記載の一般式（Ｉ）で示される化合物、その塩、そのＮ－オキシド体、その溶媒和物、またはそれらのプロドラッグの有効量を、Ｂｒｋ阻害を必要とする患者に投与することを特徴とするＢｒｋ阻害方法に関する。That is, the present invention
[1] General formula (I)

(During the ceremony,
ring1 and ring2 independently represent a C5-10 carbocycle or a 5-10-membered heterocycle, respectively.
R ¹ represents C1-4 alkyl, C2-4 alkenyl, C2-4 alkynyl, C3-6 cycloalkyl, or 3-6 member heterocycloalkyl, the C1-4 alkyl, C2-4 alkenyl, C2-4. The alkynyl, C3-6 cycloalkyl, or 3-6 member heterocycloalkyl may be substituted with 1-5 halogens or hydroxyl groups.
R ² represents halogen, C1-4 alkyl, OR ⁴ , NR ⁵ R ⁶ , or oxo, the C1-4 alkyl may be substituted with 1-5 halogens.
R ⁴ represents a hydrogen atom, C1-4 alkyl, or benzene ring, and the C1-4 alkyl or benzene ring may be substituted with 1 to 5 halogens.
R ⁵ and R ⁶ independently represent a hydrogen atom or C1-4 alkyl, respectively.
R ³ represents a halogen, C1-4 alkyl, OR ⁷ , NR ⁸ R ⁹ , SO ₂ R ¹⁰ , COR ¹¹ , benzene ring, 4-6 membered heterocycle, or oxo, the C1-4 alkyl representing a halogen. , A hydroxyl group, a 4-6 membered heterocycle, and may be substituted with 1-5 substituents selected from the group consisting of CONR ¹² R ¹³ .
R ⁷ represents a hydrogen atom or C1-4 alkyl, which C1-4 alkyl may be substituted with 1-5 halogens or NR ¹⁴ R ¹⁵ .
R ⁸ and R ⁹ independently represent a hydrogen atom, C1-4 alkyl, or acetyl, respectively.
R ¹⁰ represents C1-4 alkyl or NR ¹⁶ R ¹⁷
R ¹¹ represents a hydroxyl group, C1-4 alkyl, NR ¹⁸ R ¹⁹ , or a 4-6 membered heterocycle, the 4-6 membered heterocycle being selected from the group consisting of halogens, hydroxyl groups, and C1-4 alkyl. It may be substituted with 1 to 5 substituents.
R ¹² , R ¹³ , R ¹⁴ , R ¹⁵ , R ¹⁶ and R ¹⁷ independently represent a hydrogen atom or C1-4 alkyl, respectively.
R ¹⁸ and R ¹⁹ each independently represent a hydrogen atom, a C1-4 alkyl, or a 4-6 membered heterocycle, the C1-4 alkyl being 1-5 hydroxyls, C1-3 alkoxy, or. It may be replaced with NR ²⁰ R ²¹ .
R ²⁰ and R ²¹ independently represent a hydrogen atom or C1-4 alkyl, respectively.
p represents an integer from 0 to 7.
q represents an integer from 0 to 7.
However, when p and q each represent an integer of 2 or more, R ² and R ³ may be the same or different, respectively. )
Compounds, salts thereof, N-oxides thereof, solvates thereof, or prodrugs thereof.
[2] The above-mentioned [1], wherein R ¹ is isopropyl, tert-butyl, isobutyl, C3-6 cycloalkyl, or 3-6 member heterocycloalkyl, which may be substituted with 1 to 5 halogens or hydroxyl groups. ] Described compounds, salts thereof, N-oxides thereof, solvates thereof, or prodrugs thereof.
[3] The compound according to the above [1] or [2], wherein ring1 is a 9-10-membered nitrogen-containing bicyclic aromatic heterocycle, a salt thereof, an N-oxide compound thereof, a solvate thereof, or a prodrug thereof. drag,
[4] The compound according to any one of the above [1] to [3], wherein ring2 is a benzene ring, a salt thereof, an N-oxide form thereof, a solvate thereof, or a prodrug thereof.
[5] The compound according to any one of the above [1] to [4], wherein q is 1 or more and at least one R ³ is halogen, C1-3 alkoxy, SO ₂ R ¹⁰ , or COR ¹¹ . , The salt, the N-oxide, the solvate, or their prodrug,
[6] General formula (I-1)

(In the formula, ring1-1 represents an indole ring or an indazole ring, R ^1-1 represents isopropyl, tert-butyl, cyclobutyl, cyclopentyl, difluorocyclopentyl, oxetanyl, or tetrahydrofuranyl, X represents halogen, p- 1 represents an integer of 0 to 6, q-1 represents an integer of 0 to 4, and other symbols have the same meanings as the symbols described in [1] above.)
The compound according to the above [1], a salt thereof, an N-oxide compound thereof, a solvate thereof, or a prodrug thereof.
[7] General formula (I-1')

(In the formula, R ^3'represents SO ₂ R ¹⁰ or COR ¹¹ , and the other symbols have the same meanings as the symbols described in [1] or [6] above.)
The compound according to the above [1], a salt thereof, an N-oxide compound thereof, a solvate thereof, or a prodrug thereof.
[8]
(1) 6-Amino-7- (7-fluoro-1H-indazole-4-yl) -2-{[2-fluoro-4- (methylsulfonyl) phenyl] amino} -9-isopropyl-7,9- Dihydro-8H-purine-8-on,
(2) 6-Amino-7- (7-chloro-1H-indazole-4-yl) -2-{[2-fluoro-4- (methylsulfonyl) phenyl] amino} -9-isopropyl-7,9- Dihydro-8H-purine-8-on,
(3) 6-Amino-7- (6,7-difluoro-1H-indazole-4-yl) -2-{[2-fluoro-4- (methylsulfonyl) phenyl] amino} -9-isopropyl-7, 9-Dihydro-8H-Purin-8-on,
(4) 6-Amino-7- (7-fluoro-1H-indazole-4-yl) -2-{[2-fluoro-4- (methylsulfonyl) phenyl] amino} -9- (2-methyl-2) -Propanil) -7,9-dihydro-8H-purine-8-on,
(5) 2-[(4-Acetyl-2-fluorophenyl) amino] -6-amino-7- (1H-indazole-4-yl) -9-isopropyl-7,9-dihydro-8H-purine-8 -on,
(6) 6-Amino-9-Cyclopentyl-2-{[2-fluoro-4- (methylsulfonyl) phenyl] amino} -7- (1H-indazole-4-yl) -7,9-dihydro-8H- Pudding-8-on,
(7) 6-Amino-9-Cyclobutyl-2-{[2-fluoro-4- (methylsulfonyl) phenyl] amino} -7- (1H-indazole-4-yl) -7,9-dihydro-8H- Pudding-8-on,
(8) 6-Amino-2-{[2-fluoro-4- (methylsulfonyl) phenyl] amino} -7- (1H-indazole-4-yl) -9- (2-methyl-2-propanol)- 7,9-dihydro-8H-purine-8-on,
(9) 6-Amino-2-{[2-fluoro-4- (methylsulfonyl) phenyl] amino} -9-isopropyl-7- (7-methyl-1H-indazole-4-yl) -7,9- Dihydro-8H-purine-8-on,
(10) 6-Amino-9- (3,3-difluorocyclopentyl) -2-{[2-fluoro-4- (methylsulfonyl) phenyl] amino} -7- (1H-indazole-4-yl) -7 , 9-dihydro-8H-purine-8-on,
(11) 6-Amino-7- (7-chloro-1H-indazole-4-yl) -9-isopropyl-2-{[2-methoxy-4- (methylsulfonyl) phenyl] amino} -7,9- Dihydro-8H-purine-8-on,
(12) 6-Amino-7- (7-Fluoro-1H-Indazole-4-yl) -2-{[2-Methoxy-4- (methylsulfonyl) phenyl] amino} -9- (2-Methyl-2) -Propanil) -7,9-dihydro-8H-purine-8-on,
(13) 6-Amino-2-{[2-fluoro-4- (methylsulfonyl) phenyl] amino} -7- (1H-indole-6-yl) -9- (tetrahydro-3-furanyl) -7, 9-Dihydro-8H-Purin-8-on,
(14) 6-Amino-9-Cyclopentyl-2-{[2-fluoro-4- (methylsulfonyl) phenyl] amino} -7- (3-hydroxyphenyl) -7,9-dihydro-8H-purine-8 -on,
(15) 6-Amino-2-{[2,3-difluoro-4- (methylsulfonyl) phenyl] amino} -7- (7-fluoro-1H-indazole-4-yl) -9-isopropyl-7, 9-Dihydro-8H-Purin-8-on,
(16) 6-Amino-2-{[2,5-difluoro-4- (methylsulfonyl) phenyl] amino} -7- (7-fluoro-1H-indazole-4-yl) -9-isopropyl-7, 9-Dihydro-8H-Purin-8-on,
(17) 6-Amino-7- (3-amino-4-fluorophenyl) -2-{[2-fluoro-4- (methylsulfonyl) phenyl] amino} -9-isopropyl-7,9-dihydro-8H -Prince-8-on,
(18) 6-Amino-7- (1-benzofuran-5-yl) -2-{[2-fluoro-4- (methylsulfonyl) phenyl] amino} -9-isopropyl-7,9-dihydro-8H- Pudding-8-on,
(19) 6-Amino-2-{[2-fluoro-4- (methylsulfonyl) phenyl] amino} -7- (1H-indazole-4-yl) -9- (1,1,1-trifluoro-) 2-Propanil) -7,9-dihydro-8H-purine-8-on,
(20) 6-Amino-9-[(2S) -2-butanyl] -7- (7-fluoro-1H-indazole-4-yl) -2-{[2-fluoro-4- (methylsulfonyl) phenyl ] Amino} -7,9-dihydro-8H-purine-8-on,
(21) 6-Amino-7- (4-chloro-3-hydroxyphenyl) -9- (3,3-difluorocyclopentyl) -2-{[2-fluoro-4- (1-piperazinylcarbonyl) phenyl ] Amino} -7,9-dihydro-8H-purine-8-on,
(22) 6-Amino-7- (1H-indole-5-yl) -9-isopropyl-2-[(2-Methyl-1-oxo-2,3-dihydro-1H-isoindole-5-yl) Amino] -7,9-dihydro-8H-purine-8-on,
(23) 6-Amino-2-[(1,3-dimethyl-1H-pyrazole-4-yl) amino] -7- (1H-indole-6-yl) -9-isopropyl-7,9-dihydro- 8H-Pyrazole-8-On,
(24) 4-{[6-amino-7- (1H-indole-5-yl) -9-isopropyl-8-oxo-8,9-dihydro-7H-purin-2-yl] amino} -3- Fluoro-N, N-dimethylbenzamide,
(25) 6-Amino-9-Cyclopentyl-7- (3-Hydroxyphenyl) -2-({4- [2- (1-pyrrolidinyl) ethyl] phenyl} amino) -7,9-dihydro-8H-purine -8-on,
(26) 4-{[6-amino-9-cyclopentyl-7- (3-hydroxyphenyl) -8-oxo-8,9-dihydro-7H-purin-2-yl] amino} -3-methoxy-N , N-dimethylbenzamide,
(27) 4-{[6-amino-7- (4-chloro-3-hydroxyphenyl) -9-isopropyl-8-oxo-8,9-dihydro-7H-purin-2-yl] amino} -N -[2- (Dimethylamino) ethyl] -3-fluorobenzamide,
(28) 6-Amino-9-Cyclopentyl-2-{[2-fluoro-4- (4-morpholinylcarbonyl) phenyl] amino} -7- (3-hydroxyphenyl) -7,9-dihydro-8H -Prince-8-on,
(29) 4-{[6-amino-9-cyclopentyl-7- (3-hydroxyphenyl) -8-oxo-8,9-dihydro-7H-purin-2-yl] amino} benzamide,
(30) 6-Amino-9-Cyclopentyl-7- (3-Hydroxyphenyl) -2-{[4- (4-morpholinyl) phenyl] amino} -7,9-dihydro-8H-purine-8-on,
(31) 4-{[6-Amino-9-Cyclopentyl-7- (3-Hydroxyphenyl) -8-oxo-8,9-dihydro-7H-purin-2-yl] amino} -3-fluoro-N -(2-Hydroxyethyl) benzamide,
(32) 6-Amino-2- ({2-fluoro-4-[(4-hydroxy-1-piperidinyl) carbonyl] phenyl} amino) -7- (1H-indole-5-yl) -9- (Tetrahydro-3-furanyl) -7,9-dihydro-8H-purine-8-on,
(33) 5-{[6-amino-7- (1H-indole-5-yl) -9-isopropyl-8-oxo-8,9-dihydro-7H-purin-2-yl] amino} -N, N-dimethyl-2-pyridinecarboxamide,
(34) 6-Amino-7- (1H-indole-5-yl) -9-isopropyl-2-[(2-methyl-4-oxo-4H-chromen-7-yl) amino] -7,9- Dihydro-8H-purine-8-on,
(35) 6-Amino-7- (1H-indole-5-yl) -9-isopropyl-2-[(1-oxo-1,3-dihydro-2-benzofuran-5-yl) amino] -7, 9-Dihydro-8H-Purin-8-on,
(36) 7-{[6-amino-7- (1H-indole-5-yl) -9-isopropyl-8-oxo-8,9-dihydro-7H-purin-2-yl] amino} -4- Methyl-2H-1,4-benzoxazine-3 (4H) -one, or (37) 4-{[6-amino-7- (1H-indole-5-yl) -8-oxo-9- (tetrahydro) -3-Flanyl) -8,9-dihydro-7H-purin-2-yl] amino} -3-fluorobenzenesulfonamide The compound according to the above [1], a salt thereof, an N-oxide compound thereof, and a solvent thereof. Japanese or their prodole,
[9] A pharmaceutical composition comprising the compound represented by the general formula (I) according to the above [1], a salt thereof, an N-oxide form thereof, a solvate thereof, or a prodrug thereof as an active ingredient.
[10] The composition according to the above [9], which is a Brk inhibitor.
[11] The composition according to the above [9], which is a therapeutic agent for cancer.
[12] Cancers include breast cancer, ovarian cancer, colon cancer, lung cancer, prostate cancer, head and neck cancer, lymphoma, brain tumor, glioma, pituitary adenoma, malignant melanoma of the vine, and medullary carcinoma. Chest adenoma, mesopharyngeal tumor, esophageal cancer, gastric cancer, duodenal cancer, hepatocellular carcinoma, bile duct cancer, bile cyst cancer, pancreatic cancer, renal cell carcinoma, renal pelvis / urinary tract cancer, bladder cancer, The above-mentioned [ 11] The composition according to the above,
[13] Prevention of Brk-related diseases containing the compound represented by the general formula (I) according to the above [1], a salt thereof, an N-oxide form thereof, a solvate thereof, or a prodrug thereof as an active ingredient. / Or therapeutic agent,
[14] The therapeutic agent according to the above [13], which is a Brk-related disease.
[15] Cancers include breast cancer, ovarian cancer, colon cancer, lung cancer, prostate cancer, head and neck cancer, lymphoma, brain tumor, glioma, pituitary adenoma, malignant melanoma of the vine, and medullary carcinoma. Chest adenoma, mesopharyngeal tumor, esophageal cancer, gastric cancer, duodenal cancer, hepatocellular carcinoma, bile duct cancer, bile cyst cancer, pancreatic cancer, renal cell carcinoma, renal pelvis / urinary tract cancer, bladder cancer, The above-mentioned [ 14] The therapeutic agent according to the above,
[16] The compound represented by the general formula (I) described in [1] above, a salt thereof, an N-oxide form thereof, a solvate thereof, or a prodrug thereof, an alkylating agent, a metabolic antagonist, and an antibody thereof. Antibodies, botanicals, hormones, platinum compounds, immunomodulators, topoisomerase inhibitors, biological response regulators, kinase inhibitors, immune checkpoint inhibitors, histone deacetylase (HDAC) inhibitors , A drug in combination with at least one selected from a proteasome inhibitor, an anti-CD20 antibody, an anti-HER2 antibody, an anti-EGFR antibody, and an anti-VEGF antibody.
[17] An effective amount of the compound represented by the general formula (I) described in [1] above, a salt thereof, an N-oxide form thereof, a solvate thereof, or a prodrug thereof requires treatment for cancer. A method of treating cancer, characterized by administration to a patient
[18] A compound represented by the general formula (I) according to the above [1], a salt thereof, an N-oxide form thereof, a solvate thereof, or a prodrug thereof for the treatment of cancer.
[19] Use of the compound represented by the general formula (I) according to the above [1], a salt thereof, an N-oxide compound thereof, a solvate thereof, or a prodrug thereof for producing a therapeutic agent for cancer. , And [20] the effective amount of the compound represented by the general formula (I) described in [1] above, a salt thereof, an N-oxide form thereof, a solvate thereof, or a prodrug thereof requires Brk inhibition. The present invention relates to a Brk inhibition method comprising administration to a patient.

Since the compound of the present invention has Brk inhibitory activity and kinase selectivity, it is an excellent therapeutic agent for diseases involving Brk, for example, cancer.

Hereinafter, the present invention will be described in detail.

In the present invention, the "C5-10 carbocycle" refers to a C5-10 monocyclic or bicyclic saturated carbocycle, a C5-10 monocyclic or bicyclic unsaturated carbocycle, and a C5-10 monocyclic ring. Alternatively, it represents a bicyclic partially unsaturated carbon ring or the like. Examples of the "C5-10 carbocycle" include cyclopentane, cyclohexane, cycloheptan, cyclooctane, cyclononane, cyclodecane, cyclopentene, cyclohexene, cycloheptene, cyclooctene, cyclopentadiene, cyclohexadiene, cycloheptadiene, cyclooctadene, and the like. Benzene, pentalene, perhydropentalene, azulene, perhydroazulene, indene, perhydroinden, indane, naphthalene, dihydronaphthalene, tetrahydronaphthalene, and perhydronaphthalene rings.

In the present invention, the "5-10-membered heterocycle" refers to a 5-10-membered monocyclic or bicyclic saturated heterocycle, a 5-10-membered monocyclic or bicyclic unsaturated heterocycle, and 5-10. It represents a member monocyclic or bicyclic partially unsaturated heterocycle. Examples of the "5-10-membered heterocycle" include pyrrolidine, pyrrol, imidazole, triazole, tetrazole, pyrazole, pyridine, piperidine, piperazin, pyrazine, pyrimidine, pyridazine, azepine, diazepine, furan, pyrane, and oxazole. , Thiophen, thiopyran, thiepine, oxazole, isoxazole, thiazole, isothiazole, flazan, oxadiazole, oxazine, oxazole, oxazepine, oxadiazepine, thiazazole, thiazine, thiazidein, thiazepine, thiaziazepine, indole, isoindole, indridin, benzofuran. , Isobenzofuran, benzothiophene, isobenzothiophene, indazole, quinoline, isoquinoline, quinolidine, purine, phthalazine, pteridine, naphthylidine, quinoxalin, quinazoline, cinnoline, benzoxazole, benzothiazole, benzoimidazole, benzodioxol, benzoxazole, Clomen, benzofrazan, benzothiazyl, benzoxazole, benzotriazole, pyrrolin, pyrrolidine, imidazoline, imidazolidine, triazoline, triazolidine, tetrazoline, tetrazolidine, pyrazoline, pyrazolidine, dihydropyridine, tetrahydropyridine, dihydropyrazine, tetrahydropyrazine, dihydropyrimidine, Tetrahydropyrimidine, perhydropyrimidine, dihydropyridazine, tetrahydropyridazine, perhydropyridazine, dihydroazepine, tetrahydroazepine, perhydroazepine, dihydrodiazepine, tetrahydrodiazepine, perhydrodiazepine, dihydrofuran, tetrahydrofuran, dihydropyran, tetrahydropyran , Dihydrooxepin, Tetrahydrooxepin, Perhydrooxepin, Dihydrothiophene, Tetrahydrothiophene, Dihydrothiopyran, Tetrahydrothiopyran, Dihydrothiepine, Tetrahydrothiepine, Perhydrothiepine, Dihydrooxazole, Tetrahydrooxazole ( Oxazole), dihydroisoxazole, tetrahydroisoxazole (isoxazole), dihydrothiazole, tetrahydrothiazole (thiazolidine), dihydroisothiazole, tetrahydroisothiazole (isothiazolidine), dihydroflazan, tetrahydroflazan, Dihydrooxadiazole, tetrahydrooxadiazole (oxadiazolidine), dihydrooxazine, tetrahydrooxazine, dihydrooxadiazole, tetrahydrooxadiazine, dihydrooxazepine, tetrahydrooxazepine, perhydrooxazepine, dihydrooxadi Azepine, Tetrahydrooxadiazole, Perhydrooxadiazole, Dihydrothiadiazole, Tetrahydrothiazole (Thiadiazolezole), Dihydrothiazole, Tetrahydrothiazine, Dihydrothiazine, Tetrahydrothiazin, Dihydrothiazepine, Tetrahydrothiazepine, Perhydrothiazepine, Dihydrothiazepine, Tetrahydrothiazepine, Perhydrothiazepine, Tetrahydrotriazolopyrazine, Morpholine, Thiomorpholin, Oxadiazole, Indolin, Isoindrin, Dihydrobenzofuran, Perhydrobenzofuran, Dihydroisobenzofuran, Par Hydroisobenzofuran, dihydrobenzothiophene, perhydrobenzothiophene, dihydroisobenzothiophene, perhydroisobenzothiophene, dihydroindazole, perhydroindazole, dihydroquinoline, tetrahydroquinoline, perhydroquinoline, dihydroisoquinoline, tetrahydroisoquinolin, perhydroisoquinolin , Dihydrophthalazine, tetrahydrophthalazine, perhydrophthalazine, dihydronaphthylidine, tetrahydronaphthylidine, perhydronaphthylidine, dihydroquinoxaline, tetrahydroquinoxaline, perhydroquinoxaline, dihydroquinazoline, tetrahydroquinazoline, perhydroquinazoline, dihydrocinnoline, tetrahydrosin Norin, perhydrosinnoline, benzoxadiazole, dihydrobenzoxazine, dihydrobenzothiazine, pyrazinomorpholin, dihydrobenzoxadiazole, perhydrobenzoxadiazole, dihydrobenzothiazole, perhydrobenzothiazole, dihydrobenzoimidazole, perhydrobenzimidazole , Dioxolan, dioxane, dioxaindan, benzodioxane, thiochroman, dihydrobenzodioxin, dihydrobenzoxatiin, chromane, pyrazolopyrimidine, imidazolepyridazine, imidazolepyridine, pyrrolopyridine, imidazolepyrazine, pyrazolopyridine, imidazolepyridine, Triazolopyridine, benzopyran, phthalane, dihydrobenzoxazine, and azaindole rings.

In the present invention, the "C1-4 alkyl group" is, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, and isobutyl group.

In the present invention, the "C2-4 alkenyl group" is, for example, vinyl, 1-propenyl, 2-propenyl, 1-butenyl, 2-butenyl, 3-butenyl and the like.

In the present invention, the "C2-4 alkynyl group" is, for example, ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, 3-butynyl group and the like.

In the present invention, the "C3-6 cycloalkyl group" is a cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl group.

In the present invention, the "3-6-membered heterocycloalkyl group" refers to an oxylanyl, thiylanyl, aziridinyl, oxetanyl, thietanyl, azetidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, pyrrolidinyl, tetrahydropyranyl, tetrahydrothiopyranyl, and piperidinyl group. And so on.

In the present invention, the "halogen" is fluorine, chlorine, bromine, and iodine.

In the present invention, the "4-6 membered heterocycle" refers to a 4-6 membered monocyclic saturated heterocycle, a 4-6 membered monocyclic unsaturated heterocycle, and a 4-6 membered monocyclic partially unsaturated heterocycle. Represents a ring or the like. Examples of the "4-6-membered heterocycle" include oxetane, thietan, azetidine, tetrahydrofuran, tetrahydrothiophene, tetrahydropyran, tetrahydrothiopyran, morpholine, thiomorpholin, pyrrolidine, pyrrol, imidazole, triazole, tetrazole, pyrazole, pyridine, and the like. Piperidine, piperazine, pyrazine, pyrimidine, pyridazine, furan, pyran, thiophene, thiopyran, oxazole, isoxazole, thiazole, isothiazole, frazan, oxadiazole, oxazine, oxadiazine, thiazyl, thiazole, and thiathiazine rings, etc. Is.

In the present invention, the "C1-3 alkoxy group" is a methoxy, ethoxy, n-propoxy, and isopropoxy group.

In the present invention, the "9-10-membered nitrogen-containing bicyclic aromatic heterocycle" includes at least one nitrogen atom in addition to the carbon atom, and 1-3 selected from a nitrogen atom, an oxygen atom, and a sulfur atom. Represents a 9-10 member bicyclic aromatic heterocycle which may contain a heteroatom of. Examples of the "9-10-membered nitrogen-containing bicyclic aromatic heterocycle" include indol, indazole, benzotriazole, azaindol, pyrazolopyrimidine, benzoimidazole, benzothiazole, benzoxazole, benzoxadiazole, and benzothiadiazole. , Quinoxaline, isoquinoline, purine, phthalazine, pteridine, diazanaphthalene, quinoxaline, quinazoline, and cinnoline rings.

In the present invention, ring1 is preferably a 9-10-membered nitrogen-containing bicyclic aromatic heterocycle, more preferably indazole, indazole, benzotriazole, azaindole, pyrazolopyrimidine, benzimidazole, benzothiazole, benzoxazole, and the like. Benzoxazole, benzothiasiazole, quinoline, isoquinoline, purine, phthalazine, pteridine, naphthylidine, quinoxaline, quinazoline, or cinnoline ring, more preferably indazole, indazole, benzotriazole, azaindole, pyrazolopyrimidine, benzimidazole, It is a benzothiazole, benzoxazole, benzoxaziazole, or benzthiazazole ring, with particular preference being an indole or indazole ring.

Further, benzene or a benzofuran ring is also preferable as ring1.

In the present invention, the ring2 is preferably benzene, pyrazole, imidazole, oxazole, thiazole, pyridine, pyrimidine, pyrazine, isoindoline, or pyridazine ring, and more preferably a benzene ring.

In the present invention, R ¹ is preferably an isopropyl, tert-butyl, isobutyl, C3-6 cycloalkyl, or 3-6 member heterocycloalkyl group which may be substituted with a halogen or a hydroxyl group, and more preferably isopropyl. , Tert-Butyl, cyclobutyl, cyclopentyl, difluorocyclopentyl, oxetanyl, or tetrahydrofuranyl groups, more preferably isopropyl, tert-butyl, cyclopentyl, or difluorocyclopentyl groups, and particularly preferably isopropyl or tert-butyl groups. ..

In the present invention, R ² is preferably halogen, methyl, difluoromethyl, trifluoromethyl, methoxy, difluoromethoxy, phenoxy, hydroxyl group, amino group, or oxo, and more preferably halogen or hydroxyl group.

In the present invention, R ³ is preferably halogen, C1-4 alkyl, C1-3 alkoxy, SO ₂ R ¹⁰ , or COR ¹¹ , and more preferably halogen, SO ₂ R ¹⁰ , or COR ¹¹ . Halogen is more preferable as R ³ . Alternatively, R ³ is more preferably SO ₂ R ¹⁰ or COR ¹¹ .

In the present invention, R ⁴ is preferably a hydrogen atom, methyl, difluoromethyl, or a benzene ring.

In the present invention, R ⁵ and R ⁶ are preferably independent hydrogen atoms, methyl, or ethyl, and more preferably hydrogen atoms.

In the present invention, R ⁷ is preferably a hydrogen atom, methyl, difluoromethyl, or dimethylaminoethyl.

In the present invention, R ⁸ and R ⁹ are preferably independent hydrogen atoms or acetyls, respectively.

In the present invention, R ¹⁰ is preferably C1-4 alkyl, dimethylamino, methylamino, or amino, more preferably C1-4 alkyl, and particularly preferably methyl.

In the present invention, R ¹¹ is preferably hydroxyl group, C1-4alkyl, amino, methylamino, dimethylamino, dimethylaminoethylamino (-NHCH ₂ CH ₂ NMe ₂ ), hydroxyethylamino (-NHCH ₂ CH ₂ OH), and the like. Hydroxyethylmethylamino (-NMeCH ₂ CH ₂ OH), methoxyethylamino (-NHCH ₂ CH ₂ OME), methoxyethylmethylamino (-NMeCH ₂ CH ₂ OME), 2-hydroxy-2-methylpropylamino (-NHCH) ₂ CMe (OH) (Me)), piperidine, piperazine, methylpiperazin, pyrrolidine, or azetidine, more preferably C1-4alkyl, and particularly preferably methyl.

In the present invention, R ¹² , R ¹³ , R ¹⁴ , R ¹⁵ , R ¹⁶ and R ¹⁷ are preferably independent hydrogen atoms or methyl, respectively.

In the present invention, R ¹⁸ and R ¹⁹ are preferably independently of hydrogen atom, methyl, oxetane, dimethylaminoethyl (-CH ₂ CH ₂ NMe ₂ ), hydroxyethyl (-CH ₂ CH ₂ OH), and methoxy. Ethyl (-CH ₂ CH ₂ OME), 2-hydroxy-2-methylpropyl (-CH ₂ CMe (OH) (Me)).

In the present invention, R ²⁰ and R ²¹ are preferably independent hydrogen atoms or methyl, respectively.

In the present invention, p is preferably an integer of 0 to 4, and more preferably an integer of 0 to 2.

In the present invention, q is preferably an integer of 0 to 4, and more preferably an integer of 0 to 3.

In the present invention, the 9-10-membered nitrogen-containing bicyclic aromatic heterocycle is preferably indole, indazole, benzotriazole, azaindole, pyrazolopyrimidine, benzimidazole, benzothiazole, benzoxazole, benzoxazole, and benzothiazole. , Kinolin, isoquinolin, purine, phthalazine, pteridine, naphthylidine, quinoxalin, quinazoline, or cinnoline ring, more preferably indazole, indazole, benzotriazol, azaindole, pyrazolopyrimidine, benzimidazole, benzothiazole, benzoxazole, benzo. It is an oxadiazole or a benzothiazole ring, more preferably an indole or an indazole ring.

In the present invention, R ^1-1 is preferably an isopropyl, tert-butyl, cyclopentyl, or difluorocyclopentyl group, and more preferably an isopropyl or tert-butyl group.

In the present invention, X is preferably fluorine or chlorine, and more preferably fluorine.

In the present invention, the general formula (I) is preferably ring 1, ring 2, R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ , R ⁹ , R ¹⁰ , R. A preferred combination of definitions of ¹¹ , R ¹² , R ¹³ , R ¹⁴ , R ¹⁵ , R ¹⁶ , R ¹⁷ , R ¹⁸ , R ¹⁹ , R ²⁰ , R ²¹ , p, and q.

（式中、Ｒ^1-aは、１～５個のハロゲンまたは水酸基で置換されていてもよい、イソプロピル、ｔｅｒｔ－ブチル、イソブチル、Ｃ３－６シクロアルキル、または３－６員ヘテロシクロアルキルを表し、その他の記号は前記〔１〕記載の記号と同じ意味を表す。）で示される化合物、その塩、そのＮ－オキシド体、その溶媒和物、またはそれらのプロドラッグである。In the present invention, the general formula (I) is preferably the general formula (Ia).

(In the formula, R ^1-a represents isopropyl, tert-butyl, isobutyl, C3-6 cycloalkyl, or 3-6 member heterocycloalkyl, which may be substituted with 1-5 halogens or hydroxyl groups. , Other symbols have the same meanings as the symbols described in [1] above), their salts, their N-oxides, their solvates, or their prodrugs.

（式中、ｒｉｎｇ１－ｂは、９－１０員含窒素二環式芳香族複素環を表し、その他の記号は前記〔１〕記載の記号と同じ意味を表す。）で示される化合物、その塩、そのＮ－オキシド体、その溶媒和物、またはそれらのプロドラッグである。In the present invention, as another aspect of the general formula (I), the general formula (Ib) is preferable.

(In the formula, ring1-b represents a 9-10-membered nitrogen-containing bicyclic aromatic heterocycle, and other symbols have the same meanings as the symbols described in [1] above.) Compounds and salts thereof. , Its N-oxides, its solvates, or prodrugs thereof.

（式中、ｑ－２は０～５の整数を表し、その他の記号は前記〔１〕記載の記号と同じ意味を表す。）で示される化合物、その塩、そのＮ－オキシド体、その溶媒和物、またはそれらのプロドラッグである。In the present invention, as another aspect of the general formula (I), the general formula (Ic) is preferable.

(In the formula, q-2 represents an integer of 0 to 5, and the other symbols have the same meanings as the symbols described in [1] above.) The compound represented by the above, its salt, its N-oxide form, and its solvent. Japanese products or their pro-drugs.

（式中、Ｒ^1-dは、１～５個のハロゲンまたは水酸基で置換されていてもよい、イソプロピル、ｔｅｒｔ－ブチル、イソブチル、Ｃ３－６シクロアルキル、または３－６員ヘテロシクロアルキルを表し、ｒｉｎｇ１－ｄは９－１０員含窒素二環式芳香族複素環を表し、その他の記号は前記〔１〕記載の記号と同じ意味を表す。）で示される化合物、その塩、そのＮ－オキシド体、その溶媒和物、またはそれらのプロドラッグである。In the present invention, the general formula (I) is more preferably the general formula (Id).

(In the formula, R1 ^-d represents isopropyl, tert-butyl, isobutyl, C3-6 cycloalkyl, or 3-6 member heterocycloalkyl, which may be substituted with 1-5 halogens or hydroxyl groups. , Ring1-d represents a 9-10-membered nitrogen-containing bicyclic aromatic heterocycle, and the other symbols have the same meanings as the symbols described in [1] above.) The compound represented by the above (1), its salt, and its N-. Oxide forms, their solvates, or prodrugs thereof.

（式中、Ｒ^1-eは、１～５個のハロゲンまたは水酸基で置換されていてもよい、イソプロピル、ｔｅｒｔ－ブチル、イソブチル、Ｃ３－６シクロアルキル、または３－６員ヘテロシクロアルキルを表し、ｑ－２は０～５の整数を表し、その他の記号は前記〔１〕記載の記号と同じ意味を表す。）で示される化合物、その塩、そのＮ－オキシド体、その溶媒和物、またはそれらのプロドラッグである。In the present invention, as another aspect of the general formula (I), the general formula (I) is more preferable.

(In the formula, R ^1-e represents isopropyl, tert-butyl, isobutyl, C3-6 cycloalkyl, or 3-6 member heterocycloalkyl, which may be substituted with 1-5 halogens or hydroxyl groups. , Q-2 represents an integer of 0 to 5, and other symbols have the same meanings as the symbols described in [1] above. Or those pro-drugs.

（式中、ｒｉｎｇ１－ｆは、９－１０員含窒素二環式芳香族複素環を表し、ｑ－２は０～５の整数を表し、その他の記号は前記〔１〕記載の記号と同じ意味を表す。）で示される化合物、その塩、そのＮ－オキシド体、その溶媒和物、またはそれらのプロドラッグである。In the present invention, as another aspect of the general formula (I), the general formula (IF) is more preferable.

(In the formula, ring1-f represents a 9-10-membered nitrogen-containing bicyclic aromatic heterocycle, q-2 represents an integer of 0 to 5, and other symbols are the same as those described in [1] above. A compound represented by (meaning), a salt thereof, an N-oxide compound thereof, a solvate thereof, or a prodrug thereof.

（式中、Ｒ^1-gは、１～５個のハロゲンまたは水酸基で置換されていてもよい、イソプロピル、ｔｅｒｔ－ブチル、イソブチル、Ｃ３－６シクロアルキル、または３－６員ヘテロシクロアルキルを表し、ｒｉｎｇ１－ｇは９－１０員含窒素二環式芳香族複素環を表し、ｑ－３は０～６の整数を表し、その他の記号は前記〔１〕または〔６〕記載の記号と同じ意味を表す。）で示される化合物、その塩、そのＮ－オキシド体、その溶媒和物、またはそれらのプロドラッグであり、一般式（Ｉ）としてなお好ましくは、一般式（Ｉ－ｇ’）

（式中、Ｒ^1-gは、１～５個のハロゲンまたは水酸基で置換されていてもよい、イソプロピル、ｔｅｒｔ－ブチル、イソブチル、Ｃ３－６シクロアルキル、または３－６員ヘテロシクロアルキルを表し、ｒｉｎｇ１－ｇは９－１０員含窒素二環式芳香族複素環を表し、Ｒ^3’はＳＯ₂Ｒ¹⁰またはＣＯＲ¹¹を表し、ｑ－４は０～５の整数を表し、その他の記号は前記〔１〕または〔６〕記載の記号と同じ意味を表す。）で示される化合物、その塩、そのＮ－オキシド体、その溶媒和物、またはそれらのプロドラッグである。In the present invention, the general formula (I) is more preferably the general formula (Ig).

(In the formula, R ^1-g represents isopropyl, tert-butyl, isobutyl, C3-6 cycloalkyl, or 3-6 member heterocycloalkyl, which may be substituted with 1-5 halogens or hydroxyl groups. , Ring1-g represents a 9-10-membered nitrogen-containing bicyclic aromatic heterocycle, q-3 represents an integer of 0 to 6, and other symbols are the same as those described in [1] or [6] above. A compound represented by (meaning), a salt thereof, an N-oxide compound thereof, a solvent product thereof, or a prodrug thereof, and the general formula (I) is still more preferable as the general formula (I-g').

(In the formula, R ^1-g represents isopropyl, tert-butyl, isobutyl, C3-6 cycloalkyl, or 3-6 member heterocycloalkyl, which may be substituted with 1-5 halogens or hydroxyl groups. , Ring1-g represents a 9-10-membered nitrogen-containing bicyclic aromatic heterocycle, R ^3'represents SO ₂ R ¹⁰ or COR ¹¹ , q-4 represents an integer from 0 to 5, and other symbols. Has the same meaning as the symbol described in [1] or [6] above), a salt thereof, an N-oxide compound thereof, a solvent product thereof, or a prodrug thereof.

（式中、Ｒ^1-hは、１～５個のハロゲンまたは水酸基で置換されていてもよい、イソプロピル、ｔｅｒｔ－ブチル、イソブチル、Ｃ３－６シクロアルキル、または３－６員ヘテロシクロアルキルを表し、その他の記号は前記〔１〕または〔６〕記載の記号と同じ意味を表す。）で示される化合物、その塩、そのＮ－オキシド体、その溶媒和物、またはそれらのプロドラッグであり、一般式（Ｉ）としてなお好ましくは、一般式（Ｉ－ｈ’）

（式中、Ｒ^1-hは、１～５個のハロゲンまたは水酸基で置換されていてもよい、イソプロピル、ｔｅｒｔ－ブチル、イソブチル、Ｃ３－６シクロアルキル、または３－６員ヘテロシクロアルキルを表し、Ｒ^3’はＳＯ₂Ｒ¹⁰またはＣＯＲ¹¹を表し、ｑ－５は０～３の整数を表し、その他の記号は前記〔１〕または〔６〕記載の記号と同じ意味を表す。）で示される化合物、その塩、そのＮ－オキシド体、その溶媒和物、またはそれらのプロドラッグである。In the present invention, as another aspect of the general formula (I), the general formula (Ih) is more preferable.

(In the formula, R ^1-h represents isopropyl, tert-butyl, isobutyl, C3-6 cycloalkyl, or 3-6 member heterocycloalkyl, which may be substituted with 1-5 halogens or hydroxyl groups. , Other symbols have the same meanings as the symbols described in [1] or [6] above. The general formula (I) is still more preferable as the general formula (I-h').

(In the formula, R ^1-h represents isopropyl, tert-butyl, isobutyl, C3-6 cycloalkyl, or 3-6 member heterocycloalkyl, which may be substituted with 1-5 halogens or hydroxyl groups. , R ^3'represents SO ₂ R ¹⁰ or COR ¹¹ , q-5 represents an integer of 0 to 3, and other symbols represent the same meanings as those described in [1] or [6] above.) The compounds shown, salts thereof, N-oxides thereof, solvates thereof, or prodrugs thereof.

（式中、ｒｉｎｇ１－ｊは９－１０員含窒素二環式芳香族複素環を表し、その他の記号は前記〔１〕または〔６〕記載の記号と同じ意味を表す。）で示される化合物、その塩、そのＮ－オキシド体、その溶媒和物、またはそれらのプロドラッグであり、一般式（Ｉ）としてなお好ましくは、一般式（Ｉ－ｊ’）

（式中、ｒｉｎｇ１－ｊは９－１０員含窒素二環式芳香族複素環を表し、Ｒ^3’はＳＯ₂Ｒ¹⁰またはＣＯＲ¹¹を表し、ｑ－５は０～３の整数を表し、その他の記号は前記〔１〕または〔６〕記載の記号と同じ意味を表す。）で示される化合物、その塩、そのＮ－オキシド体、その溶媒和物、またはそれらのプロドラッグである。In the present invention, as another aspect of the general formula (I), the general formula (Ij) is more preferable.

(In the formula, ring1-j represents a 9-10-membered nitrogen-containing bicyclic aromatic heterocycle, and other symbols have the same meanings as the symbols described in [1] or [6] above.) , The salt thereof, the N-oxide compound thereof, the solvate thereof, or a prodrug thereof, and the general formula (I) is still more preferable as the general formula (I-j').

(In the equation, ring1-j represents a 9-10-membered nitrogen-containing bicyclic aromatic heterocycle, R ^3'represents SO ₂ R ¹⁰ or COR ¹¹ , q-5 represents an integer from 0 to 3. Other symbols have the same meanings as the symbols described in [1] or [6] above), their salts, their N-oxides, their solvates, or their prodrugs.

（式中、Ｒ^1-kは、１～５個のハロゲンまたは水酸基で置換されていてもよい、イソプロピル、ｔｅｒｔ－ブチル、イソブチル、Ｃ３－６シクロアルキル、または３－６員ヘテロシクロアルキルを表し、ｒｉｎｇ１－ｋは９－１０員含窒素二環式芳香族複素環を表し、ｑ－２は０～５の整数を表し、その他の記号は前記〔１〕記載の記号と同じ意味を表す。）で示される化合物、その塩、そのＮ－オキシド体、その溶媒和物、またはそれらのプロドラッグであり、一般式（Ｉ）としてなお好ましくは、一般式（Ｉ－ｋ’）

（式中、Ｒ^1-kは、１～５個のハロゲンまたは水酸基で置換されていてもよい、イソプロピル、ｔｅｒｔ－ブチル、イソブチル、Ｃ３－６シクロアルキル、または３－６員ヘテロシクロアルキルを表し、ｒｉｎｇ１－ｋは９－１０員含窒素二環式芳香族複素環を表し、Ｒ^3’はＳＯ₂Ｒ¹⁰またはＣＯＲ¹¹を表し、ｑ－５は０～３の整数を表し、その他の記号は前記〔１〕または〔６〕記載の記号と同じ意味を表す。）で示される化合物、その塩、そのＮ－オキシド体、その溶媒和物、またはそれらのプロドラッグである。In the present invention, as another aspect of the general formula (I), the general formula (Ik) is more preferable.

(In the formula, R ^1-k represents isopropyl, tert-butyl, isobutyl, C3-6 cycloalkyl, or 3-6 member heterocycloalkyl, which may be substituted with 1-5 halogens or hydroxyl groups. , Ring1-k represents a 9-10-membered nitrogen-containing bicyclic aromatic heterocycle, q-2 represents an integer of 0 to 5, and other symbols represent the same meanings as those described in [1] above. ), A salt thereof, an N-oxide compound thereof, a solvate thereof, or a prodrug thereof, and the general formula (I) is still more preferable as the general formula (I-k').

(In the formula, R ^1-k represents isopropyl, tert-butyl, isobutyl, C3-6 cycloalkyl, or 3-6 member heterocycloalkyl, which may be substituted with 1-5 halogens or hydroxyl groups. , Ring1-k represents a 9-10-membered nitrogen-containing bicyclic aromatic heterocycle, R ^3'represents SO ₂ R ¹⁰ or COR ¹¹ , q-5 represents an integer from 0 to 3, and other symbols. Has the same meaning as the symbol described in [1] or [6] above), a salt thereof, an N-oxide compound thereof, a solvent product thereof, or a prodrug thereof.

（式中、すべての記号は前記〔１〕または〔６〕記載の記号と同じ意味を表す。）で示される化合物、その塩、そのＮ－オキシド体、その溶媒和物、またはそれらのプロドラッグである。一般式（Ｉ－１）としてさらに好ましくは、ｑ－１が１以上であって、Ｒ³のうち、少なくともひとつがＳＯ₂Ｒ¹⁰またはＣＯＲ¹¹を表す。In the present invention, the general formula (I) is particularly preferably the general formula (I-1).

(In the formula, all symbols have the same meanings as the symbols described in [1] or [6] above.) A compound, a salt thereof, an N-oxide compound thereof, a solvate thereof, or a prodrug thereof. Is. More preferably, as the general formula (I-1), q-1 is 1 or more, and at least one of R ³ represents SO ₂ R ¹⁰ or COR ¹¹ .

（式中、Ｒ^3’はＳＯ₂Ｒ¹⁰またはＣＯＲ¹¹を表し、その他の記号は前記〔１〕または〔６〕記載の記号と同じ意味を表す。）で示される化合物、その塩、そのＮ－オキシド体、その溶媒和物、またはそれらのプロドラッグである。一般式（Ｉ－１’）としてさらに好ましくは、ｑ－１が１以上であって、Ｒ³のうち、少なくともひとつがハロゲンを表す。In the present invention, as another aspect of the general formula (I), the general formula (I-1') is particularly preferable.

(In the formula, R ^3'represents SO ₂ R ¹⁰ or COR ¹¹ , and other symbols have the same meanings as the symbols described in [1] or [6] above.) Compounds, salts thereof, and N thereof. -Oxidates, their solvates, or prodrugs thereof. More preferably, as the general formula (I-1'), q-1 is 1 or more, and at least one of R ³ represents a halogen.

In the present invention, as another embodiment of the general formula (I), the above general formula (Ia), general formula (Ib), general formula (Ic), and general formula (Id) are preferable. , General formula (I-e), and in the general formula selected from the group of general formula (If), when there are a plurality of R ³ independently of each other, at least two of the R ³ are halogens. And SO ₂ R ¹⁰ , or halogen and COR ¹¹ .

In the present invention, as another embodiment of the general formula (I), the compound of the present invention of Example 1 described later, the compound of the present invention of Examples 2-1 to 2-2, and Examples 3 to 3 are most preferable. 4 The compound of the present invention, or the compound of the present invention of Examples 5-1 to 5-32, a salt thereof, an N-oxide compound thereof, a solvent product thereof, or a prodrug thereof.

In the present invention, isomers include all of them unless otherwise specified. For example, alkyl groups, alkenyl groups, alkynyl groups, alkoxy groups and the like include linear and branched chains. Furthermore, isomers (E, Z, cis, trans isomers) in rings and fused rings, isomers (R, S isomers, α, β isomers, enantiomers, diastereomers) due to the presence of asymmetric carbons, etc. Optically active substances (D, L, d, l-forms), polar substances (high polar substances, low polar substances) by chromatograph separation, equilibrium compounds, rotational isomers, mixtures in any proportion thereof, racemic mixtures, etc. All are included in the present invention. The present invention also includes all isomers due to tautomerism.

は紙面の向こう側（すなわちα－配置）に結合していることを表し、

は紙面の手前側（すなわちβ－配置）に結合していることを表し、

は、α－配置とβ－配置の任意の混合物であることを表す。In the present invention, unless otherwise specified, symbols will be apparent to those skilled in the art.

Indicates that it is connected to the other side of the paper (that is, α-arrangement).

Indicates that it is connected to the front side (that is, β-arrangement) of the paper.

Represents an arbitrary mixture of α- and β-configurations.

[salt]
The compound represented by the general formula (I) is converted into a salt by a known method.

The salt is preferably a pharmaceutically acceptable salt.

The salt is preferably water-soluble.

Examples of the salt include acid addition salts, alkali metal salts, alkaline earth metal salts, ammonium salts, amine salts and the like.

Examples of the acid addition salt include hydrochloride, hydrobromide, hydroiodide, sulfate, phosphate, inorganic acid salts such as nitrate, or acetate, lactate, tartrate, and benzoic acid. Organic acid salts such as salts, citrates, methanesulfonates, ethanesulfonates, trifluoroacetates, benzenesulfonates, toluenesulfonates, isethionates, glucronates, or gluconates Can be mentioned.

Examples of the alkali metal salt include potassium salt and sodium salt.

Examples of the alkaline earth metal salt include calcium salt and magnesium salt.

Examples of the ammonium salt include tetramethylammonium salt and the like.

Examples of the amine salt include triethylamine salt, methylamine salt, dimethylamine salt, cyclopentylamine salt, benzylamine salt, phenethylamine salt, piperidine salt, monoethanolamine salt, diethanolamine salt, tris (hydroxymethyl) aminomethane salt and lysine. Examples include salts, arginine salts, and N-methyl-D-glucamine salts.

In addition, the compound of the present invention can be made into an N-oxide compound by any method. The N-oxide form represents an oxidized nitrogen atom constituting the compound represented by the general formula (I).

The compound represented by the general formula (I) and a salt thereof can also be converted into a solvate.

The solvate is preferably non-toxic and water-soluble. Suitable solvates include, for example, water, or solvates such as alcoholic solvents (eg, ethanol, etc.). The solvate also includes a solvate of the salt of the general formula (I).

[Co-crystal]
The compound represented by the general formula (I) can form a co-crystal with a suitable co-crystal forming agent. As the co-crystal, a pharmaceutically acceptable one formed with a pharmaceutically acceptable co-crystal forming agent is preferable. A co-crystal is typically defined as a crystal in which two or more different molecules are formed by an intramolecular interaction different from that of an ionic bond. Further, the co-crystal may be a complex of a neutral molecule and a salt. Cocrystals can be prepared by known methods, eg, by melt crystallization, by recrystallization from a solvent, or by physically grinding the components together. Suitable co-crystal forming agents include those described in WO2006 / 007448.

[Prodrug]
The prodrug of the compound represented by the general formula (I) means a compound converted into the compound represented by the general formula (I) by a reaction with an enzyme, gastric acid or the like in a living body. Examples of the prodrug of the compound represented by the general formula (I) include, for example, when the compound represented by the general formula (I) has an amino group, the compound in which the amino group is acylated, alkylated or phosphorylated (for example,). , The amino group of the compound represented by the general formula (I) is eicosanoylation, alanylation, pentylaminocarbonylation, (5-methyl-2-oxo-1,3-dioxolen-4-yl) methoxycarbonylation, tetrahydrofuranyl. (Pyrrolidylmethylation, pivaloyloxymethylation, acetoxymethylation, tert-butylated compound, etc.); When the compound represented by the general formula (I) has a hydroxyl group, the hydroxyl group is acylated or alkylated. Compounds that have been converted, phosphorylated, or borated (for example, the hydroxyl group of the compound represented by the general formula (I) is acetylated, palmitoylated, propanoylated, pivaloylated, succinylated, fumarylated, alanylated, dimethylaminomethylcarbonyl. (E.g., etc.); when the compound represented by the general formula (I) has a carboxy group, the compound in which the carboxy group is esterified and amidated (for example, the compound represented by the general formula (I)). The carboxy group of the compound is ethyl esterification, phenyl esterification, carboxymethyl esterification, dimethylaminomethyl esterification, pivaloyloxymethyl esterification, 1-{(ethoxycarbonyl) oxy} ethyl esterification, phthalidyl esterification, ( 5-Methyl-2-oxo-1,3-dioxolen-4-yl) methyl esterification, 1-{[(cyclohexyloxy) carbonyl] oxy} ethyl esterification, methylamidated compounds, etc.) and the like. These compounds can be produced by methods known per se. Further, the prodrug of the compound represented by the general formula (I) may be either a hydrated substance or a non-hydrated substance. Further, the prodrug of the compound represented by the general formula (I) is a general formula under physiological conditions as described in Hirokawa Shoten 1990, "Development of Pharmaceuticals", Vol. 7, "Molecular Design", pp. 163 to 198. It may be changed to the compound represented by (I).

Further, each atom constituting the compound represented by the general formula (I) has its isotope (for example, ² H, ³ H, ¹³ C, ¹⁴ C, ¹⁵ N, ¹⁶ N, ¹⁷ O, ¹⁸ O, ¹⁸ F). , ³⁵ S, ³⁶ Cl, ⁷⁷ Br, ¹²⁵ I, etc.) may be substituted.

[Method for producing the compound of the present invention]
The compound of the present invention represented by the general formula (I) can be produced according to a known method, for example, a method shown below, a method according to these, or a method shown in Examples. In each of the following production methods, the raw material compound may be used as a salt. As such a salt, those described as pharmaceutically acceptable salts of the general formula (I) are used.

（式中、Ｐ¹はベンジルまたはｐ－メトキシベンジル基を表し、その他の記号は前記〔１〕記載の記号と同じ意味を表す。）The compound of the present invention according to the general formula (I) can be produced, for example, by the method shown in the following reaction process formula.

(In the formula, P ¹ represents a benzyl or p-methoxybenzyl group, and other symbols have the same meanings as the symbols described in [1] above.)

In addition, the compound of the present invention having an amino group, a carboxy group, or a hydroxyl group can be used as a protective group generally used for these groups, for example, "Comprehensive Organic Transformations: A Guide to Functional Group Preparations 2nd Edition (2nd Edition). Richard C. Larock, John Wiley & Sons Inc, 1999) ”was used to carry out the reaction up to the Ulmann reaction described in the above reaction process formula using the compound protected by the protecting group, and then known. It can be produced by performing a deprotection reaction or, for example, the deprotection reaction described in "Comprehensive Organic Transformations: A Guide to Functional Group Preparations 2nd Edition (Richard C. Larock, John Wiley & Sons Inc, 1999)". can.

In the reaction step formula, the reaction step for producing the compound represented by the general formula (V) from the compound represented by the formula (II) can be carried out by the method described in the present specification or a known method. The compounds represented by the general formula (V) obtained by this reaction are, for example, 2,4,6-trichloro-5-nitropyrimidine (formula (II), CAS No. 4359-87-9) and the general formula (III). ) Is used for organic solvents (eg, alcohol solvents (eg, methanol, ethanol, isopropyl alcohol, butyl alcohol, etc.)), ether solvents (eg, diethyl ether, tetrahydrofuran, diethylene glycol dimethyl ether, dioxane, dimethoxy). Etan, etc.), halide-based solvents (eg, methylene chloride, chloroform, etc.), dimethylformamide, dimethylsuloxide, or a solvent in which these organic solvents are appropriately mixed, etc.) or a base in a mixed solvent of these organic solvents and water. Using a compound prepared by reacting in the presence or absence (eg, triethylamine, diisopropylethylamine, etc.) at a temperature of about −20 ° C. to 180 ° C., and an amine compound represented by the general formula (IV). Organic solvents (eg, alcohol solvents (eg, methanol, ethanol, isopropyl alcohol, butyl alcohol, etc.), ether solvents (eg, diethyl ether, tetrahydrofuran, diethylene glycol dimethyl ether, dioxane, dimethoxyethane, etc.), halide solvents (eg, dimethoxyethane, etc.) , Methylene chloride, chloroform, etc.), dimethylformamide, dimethylsuloxide, or a solvent in which these organic solvents are appropriately mixed) or a base (eg, triethylamine, diisopropylethylamine, etc.) in a mixed solvent of these organic solvents and water. Manufactured by reaction under or in the absence at a temperature of about −20 ° C to 180 ° C.

In the reaction step formula, the reaction step for producing the compound represented by the general formula (VI) from the compound represented by the general formula (V) can be carried out by the method described in the present specification or a known method. The compound represented by the general formula (VI) obtained by this reaction is, for example, an organic solvent (for example, acetic acid, ethanol, methanol, dimethylformamide, toluene, or a compound thereof, using the compound represented by the general formula (V). In a solvent in which an organic solvent is appropriately mixed) or a mixed solvent of these organic solvents and water, a catalyst (for example, iron catalyst (for example, iron, iron chloride, iron-ammonium chloride, etc.), a zinc catalyst (for example, zinc, zinc) -In the presence of an ammonium chloride (eg, nickel chloride, etc.), an indium catalyst (eg, indium, etc.), a tin solvent (eg, tin, tin chloride, etc.), or a mixture of these solvents as appropriate). , A compound (5-aminopyrimidine derivative) produced by reacting at a temperature of room temperature to about 80 ° C., or an organic solvent (eg, methanol, ethanol, ethyl acetate, tetrahydrofuran, acetic acid, 1,) under a hydrogen atmosphere. A catalyst (eg, a silver catalyst (eg, silver acetate), a platinum catalyst (eg, platinum-) in a 2-dimethoxyethane, or a solvent in which these organic solvents are appropriately mixed) or a mixed solvent of these organic solvents and water. Carbon, platinum oxide, etc.), rhodium solvents (eg, rhodium-carbon, etc.), iron solvents (eg, iron acetate, etc.), ruthenium solvents (eg, ruthenium-carbon, etc.), palladium solvents (eg, palladium-carbon, etc.), A compound produced by reacting at a temperature of room temperature to about 80 ° C. in the presence of a zinc catalyst (zinc bromide, zinc iodide, zinc acetate, etc.), lane nickel, or a catalyst in which these solvents are appropriately mixed). -Aminopyrimidine derivatives) and carbonyl compound derivatives (eg, phosgen, triphosgen, carbonyldiimidazole, carbonyldipyrrole, urea, dimethylcarbonate, diethylcarbonate, etc.) with organic solvents (eg, toluene, methylene chloride, etc.) In the presence or absence of an acid (eg, hydrochloric acid, acetic acid, etc.) or base (eg, triethylamine, pyridine, sodium methoxyd, etc.) in tetrahydrofuran, chlorobenzene, or a solvent in which these organic solvents are appropriately mixed), about-. It is manufactured by reacting at a temperature of 20 ° C to 150 ° C.

In the reaction step formula, the reaction step (Buchwald-Hartwig reaction) for producing the compound represented by the general formula (VIII) from the compound represented by the general formula (VI) is the method described in the present specification or a known method. Can be done at. The compound represented by the general formula (VIII) obtained by this reaction is, for example, an organic solvent (for example, dioxane, toluene, etc.) using the compound represented by the general formula (VI) and the compound represented by the general formula (VII). In a palladium catalyst (eg, palladium acetate, allylpalladium (II) chloride dimer (Pd ₂ Cl ₂ (allyl) ₂ ), tris (eg, dimethylformamide, N-methylpyrrolidone, or a solvent in which these organic solvents are appropriately mixed). In the presence of dibenzylideneacetone) dipalladium (0) (Pd ₂ (dba) ₃ ), etc.) and phosphorus catalysts (eg, triphenylphosphine, tributylphosphine, tricyclohexylphosphine, etc.), bases (eg, cesium carbonate, sodium butoxide, etc.) It is produced by reacting at a temperature of room temperature to about 180 ° C. in the presence of tripotassium phosphate, etc.).

In the reaction step formula, the reaction step (deprotection reaction of the protecting group of the amino group) for producing the compound represented by the general formula (IX) from the compound represented by the general formula (VIII) is described in the method described herein. Alternatively, it can be carried out by a known method, for example, the method described in Protective Groups in Organic Synthesis (T.W.Greene, John Wiley & Sons Inc. (1999)). The compound represented by the general formula (IX) obtained by this reaction is produced, for example, by using the compound represented by the general formula (VIII) by a deprotection reaction under acidic conditions or a deprotection reaction by hydrogenolysis. .. Specifically, the deprotection reaction under acidic conditions (eg, deprotection reaction of tert-butoxycarbonyl group, trityl group, p-methoxybenzyl group, etc.) is, for example, water or an organic solvent (eg, methylene chloride, etc.). Organic acids (eg acetic acid, trifluoroacetic acid, methanesulfonic acid, etc.), or inorganic acids (eg, hydrochloric acid, sulfuric acid, etc.) or mixtures thereof (eg, hydrogen bromide) in chloroform, dioxane, ethyl acetate, anisole, etc. / Acetic acid, etc.), at a temperature of about 0 ° C to 100 ° C. On the other hand, the deprotection reaction by hydrogenolysis (for example, the deprotection reaction for a benzyl group, a benzhydryl group, a benzyloxycarbonyl group, an allyloxycarbonyl group, etc.) is, for example, an organic solvent (for example, an ether solvent (for example, tetrahydrofuran, for example). Dioxane, dimethoxyethane, diethyl ether, etc.), alcohol solvent (eg, methanol, ethanol, etc.), benzene solvent (eg, benzene, toluene, etc.), ketone solvent (eg, acetone, methyl ethyl ketone, etc.), nitrile solvent (eg, acetone, methyl ethyl ketone, etc.) In a catalyst (eg, palladium-carbon, palladium black, hydroxylated, etc.) in an amide-based solvent (eg, dimethylformamide, etc.), water, ethyl acetate, acetic acid, or a mixture of two or more of them, for example). It is carried out at a temperature of about 0 ° C. to 200 ° C. in the presence of palladium, platinum oxide, lane nickel, etc.), in a hydrogen atmosphere under normal pressure or pressure, or in the presence of ammonium formate.

In the reaction step formula, the reaction step (Ullmann reaction) for producing the compound represented by the general formula (I) from the compound represented by the general formula (IX) shall be carried out by the method described in the present specification or a known method. Can be done. The compound represented by the general formula (I) obtained by this reaction is, for example, a solvent (eg, acetone, methanol, propanol) using a compound represented by the general formula (IX) and a compound represented by the general formula (X). , Acetonitrile, methylene chloride, toluene, dichloroethane, dimethylformamide, dimethylsuloxide, or a solvent in which these organic solvents are appropriately mixed) or a copper catalyst (eg, copper oxide, acetic acid) in a mixed solvent of these organic solvents and water. In the presence of copper, copper chloride, copper bromide, copper iodide, copper nitrate, etc., bases (eg, triethylamine, potassium carbonate, sodium carbonate, butoxypotassium, pyridine, dimethylaminopyridine, sodium bis (trimethylsilyl) amide, sodium acetate) , Diazabicycloundecene (DBU), diisopropylethylamine, tetramethylethylenediamine, etc.), and produced by reacting at a temperature of room temperature to about 150 ° C. In addition, there is a compound represented by the general formula (I) produced by carrying out a deprotection reaction as necessary after this Ullmann reaction. This deprotection reaction is described herein, or by known methods, such as Protective Groups in Organic Synthesis (T.W.Greene, John Wiley & Sons Inc. (1999). )) Can be done by the method described in. Specific examples of the deprotection reaction include (1) deprotection reaction by alkaline hydrolysis, (2) deprotection reaction under acidic conditions, (3) deprotection reaction by hydrogenation decomposition, and (4) metal complex. Examples thereof include a deprotection reaction using, (5) a deprotection reaction using a metal, and (6) a deprotection reaction of a silyl group. To explain each of these methods in detail, the deprotection reaction by alkaline hydrolysis (for example, the deprotection reaction of a trifluoroacetyl group) is carried out, for example, in an organic solvent (for example, methanol, tetrahydrofuran, dioxane, etc.) and alkaline. Metal hydroxides (eg, sodium hydroxide, potassium hydroxide, lithium hydroxide, etc.), alkaline earth metal hydroxides (eg, barium hydroxide, calcium hydroxide, etc.) or carbonates (eg, sodium carbonate) , Potassium carbonate, etc.) or an aqueous solution thereof or a mixture thereof, and the temperature is about 0 ° C to 40 ° C. The deprotection reaction under acid conditions (eg, deprotection reaction of butoxycarbonyl group, trityl group, etc.) is organic in, for example, water or an organic solvent (eg, methylene chloride, chloroform, dioxane, ethyl acetate, anisole, etc.). In an acid (eg, acetic acid, trifluoroacetic acid, methanesulfonic acid, etc.), or an inorganic acid (eg, hydrochloric acid, sulfuric acid, etc.) or a mixture thereof (eg, hydrogen bromide / acetic acid, etc.), about 0 ° C to 100 ° C. It is done at temperature. The deprotection reaction by hydrogenolysis (for example, the deprotection reaction for a benzyl group, a benzhydryl group, a benzyloxycarbonyl group, an allyloxycarbonyl group, etc.) is, for example, an organic solvent (for example, an ether solvent (for example, tetrahydrofuran, dioxane, etc.). Dimethoxyethane, diethyl ether, etc.), alcohol solvent (eg, methanol, ethanol, etc.), benzene solvent (eg, benzene, toluene, etc.), ketone solvent (eg, acetone, methyl ethyl ketone, etc.), nitrile solvent (eg, acetone, methyl ethyl ketone, etc.) In a catalyst (eg, palladium-carbon, palladium black, palladium hydroxide, oxidation, etc.) in an amide solvent (eg, dimethylformamide, etc.), water, ethyl acetate, acetic acid, or a mixture of two or more of them. It is carried out at a temperature of about 0 ° C. to 200 ° C. in the presence of platinum, lane nickel, etc.), in a hydrogen atmosphere under normal pressure or pressure, or in the presence of ammonium formate. Deprotection reactions using metal complexes (eg, deprotection reactions such as allyloxycarbonyl groups) include, for example, organic solvents (eg, dichloromethane, dimethylformamide, tetrahydrofuran, ethyl acetate, acetonitrile, dioxane, ethanol, etc.), water or them. Trap reagents (eg, tributyltin hydride, triethylsilane, dimedone, morpholin, diethylamine, pyrrolidine, etc.), organic acids (eg, acetic acid, formic acid, 2-ethylhexanoic acid, etc.) and / or organic acid salts (eg, acetic acid, formic acid, 2-ethylhexanoic acid, etc.) and / or organic acid salts (eg, acetic acid, formic acid, 2-ethylhexanoic acid, etc.) For example, in the presence of sodium 2-ethylhexanate, potassium 2-ethylhexanate, etc., in the presence or absence of phosphine reagents (eg, triphenylphosphine, etc.), or in the absence of metal complexes (eg, tetrakistriphenylphosphine palladium). (0), using bis (triphenylphosphine) dichloride (triphenylphosphine) palladium (II), palladium (II) acetate, tris (triphenylphosphine) rhodium (I) chloride, etc.) at a temperature of about 0 ° C to 40 ° C. Is done. The deprotection reaction using a metal is carried out, for example, in an acidic solvent (for example, acetic acid, a buffer solution having a pH of 4.2 to 7.2 or a mixture thereof and an organic solvent such as tetrahydrofuran) in the presence of powdered zinc. If necessary, it is carried out at a temperature of about 0 ° C. to 40 ° C. while applying ultrasonic waves. The deprotection reaction of the silyl group is carried out at a temperature of about 0 ° C. to 40 ° C. using, for example, tetrabutylammonium fluoride in an organic solvent miscible with water (for example, tetrahydrofuran, acetonitrile, etc.). Further, if necessary, this reaction may be followed by an operation of converting to the desired salt by a known method.

In the reaction process formula, the compounds represented by the general formulas (III), (IV), (VII), and (X) used as starting materials are known or known methods, for example, "Comprehensive Organic Transformations: A". It can be easily manufactured by using the method described in "Guide to Functional Group Preparations 2nd Edition (Richard C. Larock, John Wiley & Sons Inc, 1999)".

Among the compounds of the present invention represented by the general formula (I), for compounds other than the compounds shown above, examples described in the present specification or known methods, for example, "Comprehensive Organic Transformations: A Guide". It can be manufactured by using a combination of the methods described in "to Functional Group Preparations 2nd Edition (Richard C. Larock, John Wiley & Sons Inc, 1999)".

In each reaction herein, the reaction involving heating can be carried out using a water bath, an oil bath, a sand bath, or a microwave, as will be apparent to those skilled in the art.

In each reaction in the present specification, a solid-phase supporting reagent supported on a high molecular polymer (for example, polystyrene, polyacrylamide, polypropylene, polyethylene glycol, etc.) may be used as appropriate.

In each reaction herein, the reaction product is a conventional purification instrument, eg, distillation under normal pressure or reduced pressure, high speed liquid chromatography with silica gel or magnesium silicate, thin layer chromatography, ion exchange resin, etc. It can be purified by a scavenger resin or a method such as column chromatography or washing and recrystallization. Purification may be performed on a reaction-by-reaction basis or after several reactions have been completed.

[toxicity]
Since the compound of the present invention has low toxicity, it can be safely used as a pharmaceutical product.

[Application to pharmaceutical products]
Since the compound of the present invention exhibits Brk inhibitory activity, it is useful as a therapeutic agent for Brk-related diseases such as cancer.

More specifically, the cancers include, for example, breast cancer, ovarian cancer, colon cancer (eg, colon cancer), lung cancer (eg, non-small cell lung cancer), prostate cancer, head and neck cancer (eg, head and neck cancer). For example, oral squamous epithelial cancer, head and neck squamous epithelial cancer, pharyngeal cancer, laryngeal cancer, tongue cancer, thyroid cancer, acoustic nerve sheath tumor, etc.), lymphoma (eg, B-cell lymphoma, T-cell lymphoma, etc.) , Brain tumor, glioma, pituitary adenoma, malignant melanoma of the vine, medullary tumor, thoracic adenoma, mesenteric tumor, esophageal cancer, gastric cancer, duodenal cancer, hepatocellular carcinoma, bile duct cancer, biliary cyst cancer , Pancreatic cancer, renal cell cancer, renal pelvis / urinary tract cancer, bladder cancer, penis cancer, testis cancer, uterine cancer, vaginal cancer, genital cancer, skin cancer (eg, malignant melanoma) (Melanoma), etc.), malignant bone tumor, soft sarcoma, chondrosarcoma, leukemia (eg, acute myeloid leukemia, acute lymphocytic leukemia, chronic myeloid leukemia, chronic lymphocytic leukemia, etc.), myelodystrophy syndrome, and multiple Examples include myeloma.

In the present invention, the treatment of cancer includes reduction of tumor size, suppression of tumor growth (delay or arrest), suppression of tumor metastasis (delay or arrest), suppression of recurrence (prevention or delay), and cancer. Includes causing at least one of alleviations of one or more related symptoms.

The compound of the present invention is
1) Complementing and / or enhancing the prophylactic and / or therapeutic effect of the compound,
2) It may be administered as a concomitant drug in combination with other drugs for improving the dynamics / absorption of the compound, reducing the dose, and / or 3) reducing the side effects of the compound.

The concomitant drug of the compound of the present invention and another drug may be administered in the form of a combination drug in which both components are mixed in one preparation, or may be administered in the form of separate preparations. When the separate formulations are administered, simultaneous administration and staggered administration are included. In addition, the compound of the present invention may be administered first and the other drug may be administered later, or the other drug may be administered first and the compound of the present invention may be administered later. Each administration method may be the same or different.

The disease that exerts a preventive and / or therapeutic effect by the above-mentioned concomitant agent is not particularly limited as long as it is a disease that complements and / or enhances the preventive and / or therapeutic effect of the compound of the present invention.

Other agents for complementing and / or enhancing the therapeutic effect of the compound of the present invention on cancer include, for example, alkylating agents, antimetabolites, anticancer antibiotics, plant preparations, hormonal agents, platinum compounds. , Immunomodulators, topoisomerase inhibitors, biological response regulators, kinase inhibitors, immune checkpoint inhibitors, histon deacetylase (HDAC) inhibitors, proteasome inhibitors, anti-CD20 antibodies, anti-HER2 antibodies, anti Examples thereof include anticancer agents such as EGFR antibody and anti-VEGF antibody.

Examples of the alkylating agent include cyclophosphamide, ifosfamide, dacarbazine, nimustine hydrochloride, ranimustine, bendamustine, thiotepa, and carboquone.

Antimetabolites include, for example, methotrexate, pemetrexed, fluorouracil, tegafur, tegafur uracil, tegafur gimestat otastat potassium, doxifluridine, capecitabine, cytarabine, gemcitabine hydrochloride, fludarabin, nerarabine, carmofur, and hydrochloric acid. ..

Examples of the anticancer antibiotic include mitomycin C, doxorubicin hydrochloride, aclarubicin hydrochloride, pirarubicin hydrochloride, epirubicin, chromomycin A3, bleomycin, peplomycin sulfate, and teralubicin.

Examples of the vegetable preparation include irinotecan hydrochloride, etoposide, vincristine sulfate, vinblastine sulfate, vindesine sulfate, vinorelbine tartrate, docetaxel hydrate, eribulin mesylate, and paclitaxel.

Examples of hormonal agents include sodium estramstin phosphate, flutamide, bicalutamide, goseleline acetate, leuprorelin acetate, tamoxifen citrate, tremiphen citrate, anastrozole, retrozole, exemestane, mepitiostane, and medroxyprogesterone acetate. Examples include epithiostanol, phosfestol, fadrosole hydrochloride hydrate, avilateron, fulvestrant, and aminoglutethimide.

Examples of the platinum compound include carboplatin, cisplatin, nedaplatin, and oxaliplatin.

Examples of the immunomodulator include lenalidomide.

Examples of topoisomerase inhibitors include topotecan and sobuzoxane.

Examples of the biological response regulator include interferon gamma-1a and teceleukin.

Kinase inhibitors include, for example, EGFR inhibitors erlotinib, gefitinib, afatinib, neratinib, MEK inhibitor tramethinib, PI3K inhibitor ideraricib, JAK inhibitor luxolitinib, tofacitinib, and CDK inhibitor palbociclib. , HER2 inhibitor lapatinib, BCR-ABL inhibitor imatinib, nirotinib, bostinib, mTOR inhibitor everolimus, temsirolimus, rapamycin, ALK inhibitor crizotinib, multikinase inhibitor legorafenib, sorafenib, , And dasatinib.

Examples of immune checkpoint inhibitors include anti-CTLA-4 antibodies such as ipilimumab, tremellimumab, AGEN-1884, and anti-PD-1 antibodies such as nivolumab, pembrolizumab, REGN-2810, PDR-001, BGB-A317, and AMP-. 514 (MEDI0680), BCD-100, IBI-308, JS-001, PF-06801591, TSR-042, anti-PD-L1 antibody atezolizumab (RG7446 / MPDL3280A), avelumab (MSB0010718C), durvalumab (MEDI4736), B. -936559, CA-170, LY-3300054, anti-PD-L2 antibody rHIgM12B7, PD-L1 fusion protein, PD-L2 fusion protein AMP-224, anti-Tim-3 antibody MBG453, anti-LAG-3 Examples thereof include BMS-986016 and LAG525 which are antibodies, and Lilylumab which is an anti-KIR antibody.

Examples of histone deacetylase (HDAC) inhibitors include vorinostat, panobinostat and the like.

Examples of the proteasome inhibitor include bortezomib and the like.

Anti-CD20 antibodies include, for example, rituximab, ibritumomab, ibritumomab tiuxetan, ocrelizumab and the like.

Examples of the anti-HER2 antibody include trastuzumab, trastuzumab emtansine, and pertuzumab.

Anti-EGFR antibodies include, for example, cetuximab and panitumumab.

Examples of the anti-VEGF antibody include bevacizumab and the like.

The mass ratio of the compound of the present invention to other agents is not particularly limited.

Other agents may be administered in combination of any two or more.

In addition, other agents that complement and / or enhance the prophylactic and / or therapeutic effects of the compounds of the present invention include those found not only to date but also those found in the future based on the above-mentioned mechanism. Is done.

In order to use the compound of the present invention as a single agent or as a combination agent of the compound of the present invention and another drug for the purpose of prevention and / or treatment of the above-mentioned diseases, the substance which is an active ingredient is usually used. It is formulated with a pharmaceutically acceptable carrier such as various additives or solvents and then administered systemically or topically, orally or parenterally. Here, the pharmaceutically acceptable carrier means a substance other than the active ingredient, which is generally used for pharmaceutical preparations. The pharmaceutically acceptable carrier preferably has no pharmacological action at the dose of the preparation, is harmless, and does not interfere with the therapeutic effect of the active ingredient. The pharmaceutically acceptable carrier can also be used for the purpose of enhancing the usefulness of the active ingredient and the preparation, facilitating the formulation, stabilizing the quality, or improving the usability. Specifically, a substance as described in Yakuji Nippo's 2000 "Encyclopedia of Pharmaceutical Additives" (edited by the Japan Pharmaceutical Additives Association) may be appropriately selected according to the purpose.

Examples of the dosage form used for administration include oral preparations (eg, tablets, capsules, granules, powders, oral solutions, syrups, oral jelly, etc.), oral preparations (eg, oral tablets, etc.). Oral sprays, semi-solids for the oral cavity, gargling agents, etc.), injection formulations (eg, injections, etc.), dialysis formulations (eg, dialysis agents, etc.), inhalation formulations (eg, inhalants, etc.), Ophthalmic preparations (eg, eye drops, ointment, etc.), otologic preparations (eg, ear drops, etc.), nasal preparations (eg, nasal drops, etc.), rectal preparations (eg, suppositories, etc.) Semi-solid preparations for the rectal, intestinal injections, etc.), vaginal preparations (eg, vaginal tablets, suppositories for vagina, etc.), and skin preparations (eg, solids for external use, liquids for external use, sprays, ointments, creams, etc.) , Gel agent, patch, etc.).

[Preparation for oral administration]
The pharmaceutical product for oral administration includes, for example, tablets, capsules, granules, powders, oral solutions, syrups, oral jellies and the like. In addition, for the orally-administered preparation, a rapid-disintegrating preparation in which the release of the active ingredient from the preparation is not particularly regulated, and an enteric-coated preparation in which the release is adjusted according to the purpose by a unique formulation design and manufacturing method, for example. There are release-controlled preparations such as preparations and sustained-release preparations. Enteric-coated preparations are designed to release the active ingredient mainly in the small intestine, not in the stomach, for the purpose of preventing the decomposition of the active ingredient in the stomach or reducing the irritating effect of the active ingredient on the stomach. This is a pharmaceutical product, which can be usually produced by applying a film using an acid-insoluble enteric base. Sustained release preparation refers to a preparation in which the release rate, release time, and release site of the active ingredient from the preparation are adjusted for the purpose of reducing the number of administrations or side effects, and is usually an appropriate sustained release agent. Can be manufactured by using. Of the orally-administered preparations, capsules, granules, tablets, etc. should be coated with appropriate coating agents such as sugars, sugar alcohols, and polymer compounds for the purpose of facilitating administration or preventing decomposition of the active ingredient. It is also possible to apply a skin.

(1) Tablets Tablets are solid formulations having a certain shape that are orally administered, and are generally called tablets such as uncoated tablets, film-coated tablets, sugar-coated tablets, multi-layer tablets, and nucleated tablets. In addition, intraoral quick-disintegrating tablets, chewable tablets, effervescent tablets, dispersal tablets, dissolving tablets, etc. are included. When manufacturing an uncoated tablet, the following method (a), (b), or (c) is usually used:
(A) Add additives such as excipients, binders and disintegrants to the active ingredient, mix and homogenize, granulate with water or a solution containing the binder by an appropriate method, and then use a lubricant. Etc. are added, mixed, and compression-molded;
(B) Additives such as excipients, binders and disintegrants are added to the active ingredient and mixed to make it homogeneous. Add a swamp, etc., mix and homogenize, and then compress mold;
(C) Additives such as excipients and binders are added to the active ingredient to make them homogeneous, and the kneaded product moistened with a solvent is poured into a certain mold, molded, and then dried by an appropriate method. ;
Is used. Film-coated tablets can usually be produced by applying a thin coating to an uncoated lock with an appropriate coating agent such as a polymer compound. Sugar-coated tablets can usually be produced by applying a coating agent containing sugars or sugar alcohols to uncoated tablets. The multi-layer tablet can be produced by stacking powders and granules having different compositions in layers and compression molding by an appropriate method. The nucleated tablet can be produced by covering the inner core tablet with an outer layer having a different composition. The tablets can also be enteric-coated or sustained-release tablets using suitable known techniques. Intraoral rapid-disintegrating tablets, chewable tablets, effervescent tablets, dispersion tablets, and dissolving tablets are tablets that have been given unique functions by appropriate selection of additives, and should be manufactured according to the above-mentioned tablet manufacturing method. Can be done. Intraoral rapid disintegration tablets are tablets that can be rapidly dissolved or disintegrated in the oral cavity and taken; chewable tablets are tablets that are chewed and taken; effervescent tablets are tablets that rapidly foam in water. Dissolving or dispersing tablets; Dispersing tablets are tablets that are dispersed in water and taken; Dissolving tablets are tablets that are dissolved and taken in water. The effervescent tablet can be produced by using an appropriate acidic substance, carbonate, hydrogen carbonate or the like as an additive.

(2) Capsules Capsules are formulations that are filled in capsules or encapsulated with a capsule base, and include hard capsules, soft capsules, and the like. Hard capsules are made by adding additives such as excipients to the active ingredient to make them homogeneous, or granules or molded products by an appropriate method, and then filling the capsules as they are or by lightly molding them. It can be manufactured by doing so. Soft capsules are manufactured by encapsulating the active ingredient with additives, such as gelatin, which has increased plasticity by adding glycerin, D-sorbitol, etc., into a certain shape. can do. Capsules can be enteric or sustained release capsules using suitable known techniques, or colorants or preservatives can be added to the capsule base.

(3) Granules Granules are pharmaceuticals that are granulated into granules, and include not only granules generally called granules but also effervescent granules and the like. When producing granules, the following method (a), (b), or (c) is usually used:
(A) Excipients, binders, disintegrants, or other additives are added to the powdered active ingredient and mixed to homogenize the active ingredient, and then granulated by an appropriate method;
(B) Add an additive such as an excipient to the active ingredient prepared in the form of granules in advance and mix them to make them homogeneous;
(C) Add an additive such as an excipient to the active ingredient prepared in the form of granules in advance and mix them to form granules by an appropriate method;
Is used. The granules can be coated as needed, or can be enteric or sustained release granules using any known suitable technique. Effervescent granules can be produced by using an appropriate acidic substance, carbonate, hydrogen carbonate or the like as an additive. The effervescent granule refers to a granule that dissolves or disperses while rapidly effervescent in water. The granules can also be made into fine granules by adjusting the size of the particles.

(4) Powder The powder is a powdery preparation, and can be usually produced by adding an excipient or other additive to the active ingredient and mixing them to make them homogeneous.

(5) Oral solution The oral solution is a liquid or fluid viscous gel-like preparation, which is generally called an oral solution, as well as an elixir, a suspension, an emulsion, a limonade, and the like. included. Oral solutions can usually be produced by adding an additive and purified water to the active ingredient, mixing them to uniformly dissolve, emulsify or suspend them, and then filtering them as necessary. An elixir agent is a clear liquid oral solution containing sweet and aromatic ethanol, usually a solid active ingredient or a leachate thereof in which ethanol, purified water, a flavoring agent, and sucrose, other sugars, or It can be produced by adding a sweetener and dissolving it to make a clear liquid by filtration or other methods. A suspending agent is an oral solution in which the active ingredient is suspended in a finely homogeneous manner. Usually, a suspending agent or other additive and purified water or oil are added to a solid active ingredient and suspended by an appropriate method. , Can be manufactured by homogenizing the whole. An emulsion is an oral solution in which the active ingredient is finely and homogeneously emulsified. Usually, it can be produced by adding an emulsifier and purified water to the liquid active ingredient, emulsifying it by an appropriate method, and homogenizing the whole. .. The limonade agent is a clear liquid oral liquid agent having a sweet and sour taste.

(6) Syrup agent The syrup agent is a viscous liquid or solid preparation containing a saccharide or a sweetening agent, and includes an agent for syrup and the like. Syrups are usually dissolved, mixed, suspended, or emulsified by adding the active ingredient to a solution of syrup, other sugars, or sweeteners, or a simple syrup, and if necessary, the mixture is boiled and then heated. It can be manufactured by filtering. The syrup agent refers to a granular or powdery preparation that becomes a syrup agent when water is added, and may also be referred to as a dry syrup agent. The syrup preparation can usually be produced by using a saccharide or a sweetening agent as an additive according to the method for producing granules or powders.

(7) Oral jelly agent An oral jelly agent is a non-fluid, molded gel-like preparation, which is usually mixed with an additive and a polymer gel base by adding an additive and a polymer gel base to the active ingredient, and gelled by an appropriate method. It can be manufactured by molding into a certain shape.

[Oral formulation]
(1) Oral tablets The oral tablets are solid preparations having a certain shape to be applied to the oral cavity, and include troches, sublingual tablets, buccal tablets, adhesive tablets, gum agents and the like. Oral tablets can usually be produced according to the above-mentioned tablet production method. The troche agent is an oral tablet that is gradually dissolved or disintegrated in the oral cavity and applied locally to the oral cavity, pharynx, etc .; The sublingual tablet is an oral mucosa that rapidly dissolves the active ingredient under the tongue. An oral tablet that is absorbed from the oral cavity; a buccal tablet is an oral tablet that gradually dissolves the active ingredient between the molars and the cheek and is absorbed through the oral mucosa; Tablets for oral use; Gum agents are oral tablets that release the active ingredient by chewing.

(2) Oral spray agent An oral spray agent is a formulation that sprays the active ingredient in the form of a mist, powder, foam, or paste, and usually dissolves or suspends the active ingredient and additives in a solvent or the like. After turbidity and filtering as needed, the container is filled with liquefied gas or compressed gas, or a solution or suspension is prepared using the active ingredient and additives, and the container is filled with a spray pump. Can be manufactured by attaching.

(3) Semi-solid agent for oral cavity The semi-solid agent for oral cavity is a preparation applied to the oral mucosa and includes a cream agent, a gel agent, an ointment agent and the like. Semi-solids for the oral cavity are usually made by emulsifying the active ingredient with an additive in purified water and an oily ingredient such as petrolatum, or by mixing a polymer gel or fat as a base with the active ingredient and the additive to make it homogeneous. It can be manufactured by. The cream agent refers to a semi-solid preparation emulsified into an oil-in-water type or a water-in-oil type, and a lipophilic preparation emulsified in a water-in-oil type may also be referred to as an oil-based cream preparation. The cream is usually made of vaseline, higher alcohol, etc. as it is, or an additive such as an emulsifier is added to make an oil phase, and purified water is used as it is, or an additive such as an emulsifier is added to make an aqueous phase. It can be produced by adding an active ingredient to each of the phases, heating each of them, and stirring the oil phase and the aqueous phase together until the whole becomes homogeneous and emulsifying. The gel agent refers to a gel-like preparation, and includes an aqueous gel agent, an oil-based gel agent, and the like. The aqueous gel preparation can be produced by adding a polymer compound, other additives and purified water to the active ingredient to dissolve or suspend it, and then heating and cooling it, or adding a gelling agent to crosslink it. The oily gel agent can be produced by adding a liquid oily base such as glycols and higher alcohols and other additives to the active ingredient and mixing them. The ointment is a semi-solid preparation in which the active ingredient is dissolved or dispersed in a base, and includes oil-based ointments, water-soluble ointments and the like. Oily ointments are usually made by heating and melting oily bases such as oils and fats, waxes, and hydrocarbons such as paraffin, adding the active ingredient, mixing and dissolving or dispersing, and the whole is homogeneous. It can be manufactured by mixing and kneading until it becomes. A water-soluble ointment can usually be produced by heating and melting a water-soluble base such as macrogol, adding an active ingredient, mixing and kneading until the whole becomes homogeneous.

(4) Gargling agent The mouthwash is a liquid preparation that is applied locally to the oral cavity, pharynx, etc., and also includes a solid preparation that is dissolved and used before use. The gargling agent can usually be produced by adding a solvent and an additive to the active ingredient, mixing them, dissolving them homogeneously, and filtering if necessary. In the case of a solid preparation that is dissolved and used before use, it can usually be produced according to the production method for tablets or granules.

[Injectable product]
(1) Injections Injections are solutions, suspensions, or emulsions that are directly administered to internal tissues and organs such as subcutaneous, intramuscular, or blood vessels, or solids that are dissolved or suspended before use. In addition to lyophilized injections, powder injections, filled syringes, cartridges, infusions, implantable injections, and sustained injections, as well as sterile preparations of the above, commonly referred to as injections. Is done. When producing an injectable preparation, the following method (a) or (b) is usually used:
(A) The active ingredient as it is, or the active ingredient with an additive added, is dissolved, suspended, or emulsified in water for injection, another aqueous solvent, or a non-aqueous solvent to make it homogeneous for injection. Fill the container, seal and sterilize;
(B) The active ingredient as it is, or the active ingredient with an additive added, is dissolved, suspended, or emulsified in water for injection, another aqueous solvent, a non-aqueous solvent, etc., and homogenized is filtered aseptically. Alternatively, aseptically prepared and homogenized, the injection container is filled and sealed;
Is used. Freeze-dried injections are usually lyophilized as is, or by dissolving the active ingredient and additives such as excipients in water for injection, sterile filtering, filling in a container for injection and then lyophilizing. It can be manufactured by freeze-drying in a dedicated container and then filling the container directly. The powder injection can be usually produced by treating the powder by aseptic filtration, adding the powder obtained by crystallization or a sterilized additive to the powder, and filling the container for the injection. Filled syringes can usually be produced by preparing a solution, suspension, or emulsion with the active ingredient as is or with the active ingredient and additives and filling the syringe barrel. A cartridge agent is an injection that is used by putting a cartridge filled with a chemical solution into a dedicated syringe, and a cartridge filled with a chemical solution is usually a solution of the active ingredient as it is or using an active ingredient and an additive. It can be produced by preparing a suspension or an emulsion and filling it in a cartridge. An infusion solution is an injection usually administered intravenously in an amount of 100 mL or more. Implantable injection refers to a solid or gel-like injection that is applied subcutaneously, intramuscularly, etc. using an implantable device or surgically for the purpose of releasing the active ingredient for a long period of time. Implantable injections are usually made from biodegradable polymer compounds and can be made into pellets, microspheres, or gels. A long-acting injection is an injection that is applied intramuscularly for the purpose of releasing the active ingredient for a long period of time. Usually, the active ingredient is dissolved or suspended in vegetable oil or the like, or a biodegradable high molecular compound. It can be produced by preparing a suspension of microspheres using.

[Dialysis product]
(1) Dialysis agent The dialysis agent is a liquid or solid preparation used for peritoneal dialysis or hemodialysis and which dissolves at the time of use, and includes a peritoneal dialysis agent and a hemodialysis agent. The peritoneal dialysis agent is a sterile dialysis agent used for peritoneal dialysis. Usually, an additive is added to the active ingredient and dissolved in a solvent to make a constant volume, or an additive is added to the active ingredient. Can be manufactured by filling a container, sealing it, and sterilizing it if necessary. In the case of a solid preparation that dissolves at the time of use, it can usually be produced according to the production method for tablets or granules. A hemodialysis agent is a dialysis agent used for hemodialysis, and is usually a container in which an additive is added to an active ingredient and dissolved in a solvent to make a constant volume, or an active ingredient with an additive added. Can be manufactured by filling in. In the case of a solid preparation that dissolves at the time of use, it can usually be produced according to the production method for tablets or granules.

[Inhalation product]
(1) Inhalant The inhalant is a preparation that inhales the active ingredient as an aerosol and applies it to the bronchus or lungs, and includes powder inhalants, inhalation solutions, inhalation aerosols, and the like. A powder inhaler is a preparation that is prepared so that the inhalation amount is constant and is inhaled as an aerosol of solid particles. Usually, the active ingredient is made into fine particles and mixed with an additive such as lactose as necessary. It can be manufactured by making it homogeneous. An inhalant is a liquid inhaler applied by a nebulizer or the like. Usually, a solvent, an appropriate tonicity agent, a pH adjuster, etc. are added to the active ingredient, and the mixture is mixed and uniformly dissolved or suspended, if necessary. It can be manufactured by filtering accordingly. The inhalation aerosol agent is a fixed-quantity spray-type inhalant that sprays a certain amount of the active ingredient together with the propellant filled in the container. Inhalation aerosols are usually prepared by adding a solvent, a suitable dispersant, a stabilizer, etc. to the active ingredient to make a solution or suspension, filling a pressure-resistant container with a liquid propellant, and installing a metering valve. It can be manufactured by.

[Ophthalmic preparation]
(1) Eye drops An eye drop is a solid sterile preparation that is applied to eye tissues such as the conjunctival sac and is used in liquid form or dissolved or suspended before use. Eye drops can usually be produced by adding an additive to an active ingredient and dissolving or suspending it in a solvent or the like to have a constant volume, or by filling a container with an additive added to the active ingredient. ..

(2) Ophthalmic ointment Ophthalmic ointment is a semi-solid sterile preparation applied to ocular tissues such as the conjunctival sac, and is usually made homogeneous by mixing a base such as petrolatum with a solution of the active ingredient or fine powder. , Can be manufactured by filling in a container.

[Pharmaceutical preparation]
(1) Ear drops The ear drops are liquid, semi-solid, or solid formulations that are used by dissolving or suspending at the time of use, which are administered to the outer or middle ear. Ear drops are usually produced by adding an additive to an active ingredient and dissolving or suspending it in a solvent or the like to make it a constant volume, or by filling a container with an additive added to an active ingredient. can.

[Pharmaceutical product]
(1) Nasal drops Nasal drops are formulations that are administered to the nasal cavity or nasal mucosa, and include nasal powders, nasal drops, and the like. Nasal drop powder refers to a fine powdery nasal drop that is administered to the nasal cavity, and is usually produced by making the active ingredient into moderately fine particles and mixing them with additives as necessary to make them homogeneous. Can be done. Nasal drops are liquid nasal drops that are administered to the nasal cavity, or solid nasal drops that are used by dissolving or suspending at the time of use. It can be manufactured by filtering according to the above. As the additive for the nasal drops, an tonicity agent, a pH adjuster and the like can be used.

[Preparation for rectum]
(1) Suppository A suppository is a semi-solid preparation having a certain shape, which is applied to the rectum and melts at body temperature or gradually dissolves or disperses in water to release an active ingredient. Suppositories are usually prepared by adding additives such as dispersants and emulsifiers to the active ingredient and mixing them to make them uniform, and then dissolving or uniformly dispersing them in a base that has been liquefied by heating or the like to make a container. It can be manufactured by filling a certain amount of the product and solidifying / molding the product. As the base of the suppository, an oily base or a hydrophilic base is usually used.

(2) Semi-solid preparation for rectum The semi-solid preparation for rectum is a preparation applied around or in the anus, and includes a cream for rectum, a gel for rectum, an ointment for rectum, and the like. Semi-solid preparations for the rectal are usually made homogeneous by emulsifying the active ingredient with an additive in purified water and an oily ingredient such as petrolatum, or by mixing a polymer gel or fat as a base with the active ingredient and the additive. It can be manufactured by. The rectal cream is usually prepared by using vaseline, higher alcohol, etc. as it is or adding an additive such as an emulsifier to make an oil phase, and separately using purified water as it is or adding an additive such as an emulsifier to make an aqueous phase. It can be produced by adding an active ingredient to either phase, heating each of them, stirring the oil phase and the aqueous phase together until the whole becomes homogeneous, and emulsifying the mixture. The rectal gel agent refers to a gel-like preparation, and includes an aqueous gel agent, an oil-based gel agent, and the like. The aqueous gel preparation can be produced by adding a polymer compound, other additives and purified water to the active ingredient to dissolve or suspend it, and then heating and cooling it, or adding a gelling agent to crosslink it. The oily gel agent can be produced by adding a liquid oily base such as glycols and higher alcohols and other additives to the active ingredient and mixing them. The rectal ointment is a semi-solid preparation in which the active ingredient is dissolved or dispersed in a base, and includes oily ointment, water-soluble ointment and the like. Oily ointments are usually made by heating and melting oily bases such as oils and fats, waxes, and hydrocarbons such as paraffin, adding the active ingredient, mixing and dissolving or dispersing, and the whole is homogeneous. It can be manufactured by mixing and kneading until it becomes. A water-soluble ointment can usually be produced by heating and melting a water-soluble base such as macrogol, adding an active ingredient, mixing and kneading until the whole becomes homogeneous.

(3) Enema The enema is a liquid or viscous gel-like preparation that is applied through the anus, and the active ingredient is usually dissolved or suspended in a solvent or the like using purified water or an appropriate aqueous solvent. It can be manufactured by making it a constant capacity and filling it in a container. As the additive for the intestinal injection, a dispersant, a stabilizer, a pH adjuster and the like can be used.

[Vaginal preparation]
(1) Vaginal tablets Vaginal tablets are solid formulations of a certain shape that are applied to the vagina and release the active ingredient by gradually dissolving or dispersing in water, and are usually manufactured according to the above-mentioned tablet manufacturing method. can do.

(2) Vaginal suppository A vaginal suppository is a semi-solid preparation of a certain shape that is applied to the vagina and releases the active ingredient by melting with body temperature or gradually dissolving or dispersing in water. , Usually, it can be produced according to the production method of the rectal suppository and the like.

[Skin preparation]
(1) External solid agent The external solid agent is a solid preparation that is applied or sprayed on the skin or nails including the scalp, and includes an external powder and the like. The external powder is a powdered external solid, and can be usually produced by adding an additive such as an excipient to the active ingredient, mixing them to make them homogeneous, and then making them into a powder.

(2) External solution The external solution is a liquid preparation to be applied to the skin or nails including the scalp, and includes a liniment agent, a lotion agent and the like. The external liquid preparation can usually be produced by adding a solvent, an additive or the like to the active ingredient, dissolving, emulsifying or suspending the liquid, and filtering if necessary. The liniment agent is a liquid or muddy external liquid agent that is used by rubbing it on the skin. A lotion is an external solution in which the active ingredient is dissolved, emulsified, or finely dispersed in an aqueous solution, and is usually a solution, suspension, or emulsion using the active ingredient, additives, and purified water. It can be produced by homogenizing the whole as a liquid.

(3) Spray agent The spray agent is a preparation that sprays the active ingredient onto the skin in the form of a mist, powder, foam, paste, or the like, and includes an external aerosol agent, a pump spray agent, and the like. Sprays can usually be produced by preparing a solution or suspension of the active ingredient, filtering if necessary, and then filling the container. An external aerosol agent is a spray agent that sprays an active ingredient together with a liquefied gas or a compressed gas filled in a container. The external aerosol agent can usually be produced by preparing a solution or suspension of the active ingredient, filling it in a pressure-resistant container together with a liquid propellant, and attaching a continuous injection valve. Additives such as a dispersant and a stabilizer can be added to the external aerosol agent, if necessary. The pump spray agent is a spray agent that sprays the active ingredient in the container with a pump. Pump sprays can usually be produced by dissolving or suspending the active ingredient and additives and mounting the pump in a filled container.

(4) Ointment The ointment is a semi-solid preparation to which the active ingredient is dissolved or dispersed in a base, which is applied to the skin, and includes an oily ointment, a water-soluble ointment and the like. Oily ointments are usually made by heating and melting oily bases such as oils and fats, waxes, and hydrocarbons such as paraffin, adding the active ingredient, mixing and dissolving or dispersing, and the whole is homogeneous. It can be manufactured by mixing and kneading until it becomes. A water-soluble ointment can usually be produced by heating and melting a water-soluble base such as macrogol, adding an active ingredient, mixing and kneading until the whole becomes homogeneous.

(5) Cream agent A cream agent is a semi-solid preparation emulsified into an oil-in-water type or a water-in-oil type to be applied to the skin, and a lipophilic preparation emulsified in a water-in-oil type is also called an oil-based cream agent. Sometimes. The cream is usually made of vaseline, higher alcohol, etc. as it is, or an additive such as an emulsifier is added to make an oil phase, and purified water is used as it is, or an additive such as an emulsifier is added to make an aqueous phase. It can be produced by adding an active ingredient to each of the phases, heating each of them, and stirring the oil phase and the aqueous phase together until the whole becomes homogeneous and emulsifying.

(6) Gel agent The gel agent is a gel-like preparation to be applied to the skin, and includes an aqueous gel agent, an oil-based gel agent and the like. The aqueous gel preparation can be produced by adding a polymer compound, other additives and purified water to the active ingredient to dissolve or suspend it, and then heating and cooling it, or adding a gelling agent to crosslink it. The oily gel agent can be produced by adding a liquid oily base such as glycols and higher alcohols and other additives to the active ingredient and mixing them.

(7) Patching agent The patching agent is a preparation to be attached to the skin, and includes a tape agent, a vap agent, and the like. The patch can usually be produced by using a polymer compound or a mixture thereof as a base, mixing the active ingredient with the base, making it homogeneous, and spreading it on a support or a liner (peeling body) to form the patch. can. In addition, a transdermal preparation can be prepared by using a release-regulating membrane. If necessary, additives such as adhesives and absorption promoters can be used as the patch. The tape agent is a patch that uses a base that contains almost no water, and includes plaster agents, plaster agents, and the like. The tape agent is usually based on a water-insoluble natural or synthetic polymer compound such as resin, plastic, or rubber, and the active ingredient is used as it is, or an additive is added to the active ingredient to homogenize the whole and spread on a cloth. It can be manufactured by spreading or enclosing it in a rolled or plastic film or the like and molding it. It can also be produced by encapsulating a mixture consisting of an active ingredient and a base or other additives in a release body made of a release control membrane, a support and a liner (peeling body) and molding the mixture. A bopping agent is a patch that uses a base containing water. Usually, the active ingredient is mixed with purified water, liquid substances such as glycerin to make the whole homogeneous, or a water-soluble polymer and high water absorption. It can be produced by mixing a natural or synthetic polymer compound such as a molecule with purified water, kneading it, adding an active ingredient, homogenizing the whole, spreading it on a cloth or the like, and molding it.

Hereinafter, the present invention will be described in detail by way of examples, but the present invention is not limited thereto.

The location of the separation by chromatography and the solvent in parentheses shown in the TLC indicate the elution solvent or developing solvent used, and the ratio represents the volume ratio.

The solvent in parentheses shown in the NMR section indicates the solvent used for the measurement.
LC-MS / ELSD has the following conditions:
Condition 1
{Column: Waters ACQUITY C ₁₈ (particle size: 1.7 x 10 ^-6 m; column length: 30 x 2.1 mm ID); flow velocity: 1.0 mL / min; column temperature: 40 ° C.; mobile phase (A): 0. 1% formic acid aqueous solution; mobile phase (B): 0.1% formic acid-acetography solution; gradient (state the ratio of mobile phase (A): mobile phase (B)): [0 min] 95: 5; [ 0.1 min] 95: 5; [1.2 min] 5:95; [1.4 min] 5:95; [1.41 min] 95: 5; [1.5 min] 95: 5; detection Vessel: UV (PDA), ELSD, MS}
Condition 2
{Column: YMC Triart C ₁₈ (particle size: 1.9 x 10 ^-6 m; column length: 30 x 2.0 mm ID); flow velocity: 1.0 mL / min; column temperature: 30 ° C.; mobile phase (A): 0. 1% trifluoroacetic acid aqueous solution; mobile phase (B): 0.1% trifluoroacetic acid-acetoform solution; gradient (state the ratio of mobile phase (A): mobile phase (B)): [0 min] 95: 5 [0.1 min] 95: 5; [1.2 min] 5:95; [1.4 min] 5:95; [1.41 min] 95: 5; [1.5 min] 95: 5 Detector: UV (PDA), ELSD, MS}.

The compound names used in the present specification are generally ACD / Name (registered trademark), a computer program for naming according to the IUPAC rules, or Chemdraw Ultra (version 12.0, manufactured by Cambridge Soft). Or named according to the IUPAC nomenclature.

２，４，６－トリクロロ－５－ニトロピリミジン（ＣＡＳ Ｎｏ．４３５９－８７－９、２２．８ｇ）の塩化メチレン（１７０ｍＬ）溶液に、ｔｅｒｔ－ブチルアミン(７．３ｇ)の塩化メチレン（３０ｍＬ）溶液を、０℃でゆっくり滴下した。反応混合物にジイソプロピルエチルアミン（１７．３ｍＬ）を０℃でゆっくり滴下した。反応混合物を０℃で６０分間撹拌した。反応混合物に水を注ぎ、塩化メチレンで抽出した。得られた有機層を飽和食塩水で洗浄し、硫酸ナトリウムにて乾燥後、減圧濃縮した。得られた中間体（２７．８ｇ）の内１２．７ｇを塩化メチレン（１７０ｍＬ）に溶解した。その溶液にジベンジルアミン（１９．２ｍＬ）の塩化メチレン（３０ｍＬ）溶液を、０℃で滴下した。反応混合物にジイソプロピルエチルアミン（１７．３ｍＬ）を０℃で滴下した。反応混合物を０℃で６０分間撹拌した。反応混合物に水を注ぎ、塩化メチレンで抽出した。得られた有機層を飽和食塩水で洗浄し、硫酸ナトリウムにて乾燥後、減圧濃縮した。残りの中間体（１５．０９ｇ）も同様に反応した。得られた粗目的物をシリカゲルカラムクロマトグラフィーで精製することより、以下の物性値を有する標題化合物（２７．２ｇ）を得た。
ＴＬＣ：Ｒｆ ０．４５（ヘキサン：酢酸エチル＝９：１）；
¹Ｈ－ＮＭＲ（ＣＤＣｌ₃）：δ 1.51, 4.52, 7.06-7.14, 7.23-7.38, 8.41。Reference Example 1: N, N-dibenzyl-N'-tert-butyl-2-chloro-5-nitropyrimidine-4,6-diamine

A solution of 2,4,6-trichloro-5-nitropyrimidine (CAS No. 4359-87-9, 22.8 g) in methylene chloride (170 mL) and a solution of tert-butylamine (7.3 g) in methylene chloride (30 mL). Was slowly added dropwise at 0 ° C. Diisopropylethylamine (17.3 mL) was slowly added dropwise to the reaction mixture at 0 ° C. The reaction mixture was stirred at 0 ° C. for 60 minutes. Water was poured into the reaction mixture and the mixture was extracted with methylene chloride. The obtained organic layer was washed with saturated brine, dried over sodium sulfate, and concentrated under reduced pressure. Of the obtained intermediate (27.8 g), 12.7 g was dissolved in methylene chloride (170 mL). A solution of dibenzylamine (19.2 mL) in methylene chloride (30 mL) was added dropwise to the solution at 0 ° C. Diisopropylethylamine (17.3 mL) was added dropwise to the reaction mixture at 0 ° C. The reaction mixture was stirred at 0 ° C. for 60 minutes. Water was poured into the reaction mixture and the mixture was extracted with methylene chloride. The obtained organic layer was washed with saturated brine, dried over sodium sulfate, and concentrated under reduced pressure. The remaining intermediate (15.09 g) reacted in the same manner. The obtained crude product was purified by silica gel column chromatography to give the title compound (27.2 g) having the following physical characteristics.
TLC: Rf 0.45 (hexane: ethyl acetate = 9: 1);
^{1 1} H-NMR (CDCl ₃ ): δ 1.51, 4.52, 7.06-7.14, 7.23-7.38, 8.41.

塩化アンモニウム（２０．８ｇ）を水（１５６ｍＬ）に溶解し、亜鉛（４２．４ｇ）と混合した。この懸濁液に参考例１で製造された化合物（２７．６ｇ）の酢酸エチル（４６７ｍＬ）溶液を室温で滴下し、室温で４時間撹拌した。反応混合物をセライト（商品名）でろ過し、セライトを水および酢酸エチルで洗浄した。ろ液を酢酸エチルで抽出した。得られた有機層を水および飽和食塩水で洗浄し、硫酸ナトリウムにて乾燥後、減圧濃縮した。得られた残渣にテトラヒドロフラン（２７６ｍＬ）を加えた。得られた溶液に、１，１’－カルボニルジイミダゾール(２２．３ｇ)とジアザビシクロウンデセン（ＤＢＵ；１０．３ｍＬ）を加えた。反応混合物を室温で１時間撹拌した。反応混合物に１Ｎ塩酸を加え、酢酸エチルで抽出した。得られた有機層を、水、飽和炭酸水素ナトリウム水溶液、および飽和食塩水で洗浄した。得られた有機層を硫酸ナトリウムにて乾燥後、減圧濃縮した。得られた残渣をメチル－ｔｅｒｔ－ブチルエーテル（ＭＴＢＥ）で洗浄して、ろ取した。ろ取物を乾燥することより、以下の物性値を有する標題化合物（２３．３ｇ）を得た。
ＴＬＣ：Ｒｆ ０．４０（ヘキサン：酢酸エチル＝４：１）；
¹Ｈ－ＮＭＲ（ＣＤＣｌ₃）：δ 1.70, 4.76, 7.22-7.40, 8.16。Reference Example 2: 9-tert-Butyl-2-chloro-6- (dibenzylamino) -7,9-dihydro-8H-purine-8-one

Ammonium chloride (20.8 g) was dissolved in water (156 mL) and mixed with zinc (42.4 g). A solution of the compound (27.6 g) prepared in Reference Example 1 in ethyl acetate (467 mL) was added dropwise to this suspension at room temperature, and the mixture was stirred at room temperature for 4 hours. The reaction mixture was filtered through Celite (trade name) and the Celite was washed with water and ethyl acetate. The filtrate was extracted with ethyl acetate. The obtained organic layer was washed with water and saturated brine, dried over sodium sulfate, and concentrated under reduced pressure. Tetrahydrofuran (276 mL) was added to the obtained residue. To the resulting solution was added 1,1'-carbonyldiimidazole (22.3 g) and diazabicycloundecene (DBU; 10.3 mL). The reaction mixture was stirred at room temperature for 1 hour. 1N Hydrochloric acid was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The resulting organic layer was washed with water, saturated aqueous sodium hydrogen carbonate solution, and saturated brine. The obtained organic layer was dried over sodium sulfate and then concentrated under reduced pressure. The obtained residue was washed with methyl-tert-butyl ether (MTBE) and collected by filtration. By drying the filtrate, the title compound (23.3 g) having the following physical characteristics was obtained.
TLC: Rf 0.40 (hexane: ethyl acetate = 4: 1);
^{1 1} H-NMR (CDCl ₃ ): δ 1.70, 4.76, 7.22-7.40, 8.16.

参考例２で製造された化合物（１２７ｍｇ）、２－フルオロ－４－メチルスルホニルアニリン（６２ｍｇ）、および炭酸セシウム（２９３ｍｇ）のジメトキシエタン（０．９ｍＬ）溶液を脱気して、アルゴン置換した。２－（ジシクロヘキシルホスフィノ）－２’，４’，６’－トリイソプロピルビフェニル（２９ｍｇ）とトリス（ジベンジリデンアセトン）ジパラジウム（０）（２８ｍｇ）を加えた。反応混合物を８５℃で１６時間撹拌した。反応混合物に水を加えて、酢酸エチルで抽出した。得られた有機層を飽和食塩水で洗浄した。得られた有機層を硫酸ナトリウムにて乾燥後、減圧濃縮した。得られた残渣をシリカゲルカラムクロマトグラフィーで精製することにより、下記物性値を有する標題化合物（１５３ｍｇ）を得た。
ＴＬＣ：Ｒｆ ０．２３（ヘキサン：酢酸エチル＝２：１）；
¹Ｈ－ＮＭＲ（ＣＤＣｌ₃）：δ 1.72, 3.02, 4.82, 7.15-7.18, 7.22-7.39, 7.41-7.45, 7.57-7.62, 8.45-8.52, 9.07。Reference Example 3: 9-tert-butyl-6- (dibenzylamino) -2-{[2-fluoro-4- (methylsulfonyl) phenyl] amino} -7,9-dihydro-8H-purine-8-on

A solution of the compound (127 mg) prepared in Reference Example 2, 2-fluoro-4-methylsulfonylaniline (62 mg), and cesium carbonate (293 mg) in dimethoxyethane (0.9 mL) was degassed and substituted with argon. 2- (Dicyclohexylphosphino) -2', 4', 6'-triisopropylbiphenyl (29 mg) and tris (dibenzylideneacetone) dipalladium (0) (28 mg) were added. The reaction mixture was stirred at 85 ° C. for 16 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The obtained organic layer was washed with saturated brine. The obtained organic layer was dried over sodium sulfate and then concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography to give the title compound (153 mg) having the following physical characteristics.
TLC: Rf 0.23 (hexane: ethyl acetate = 2: 1);
^{1 1} H-NMR (CDCl ₃ ): δ 1.72, 3.02, 4.82, 7.15-7.18, 7.22-7.39, 7.41-7.45, 7.57-7.62, 8.45-8.52, 9.07.

窒素雰囲気下、参考例３で製造された化合物（１６３ｍｇ）をエタノール（１．１ｍＬ）およびテトラヒドロフラン（０．３ｍＬ）に溶解して、２０％水酸化パラジウム炭素（８０ｍｇ）を加えた。水素雰囲気下、反応混合物を６０℃で６時間撹拌させた後、セライト（商品名）でろ過して、セライトを塩化メチレン／メタノールで洗浄した。ろ液を減圧濃縮した。得られた残渣を酢酸エチルで固化させて、固体をろ取した。ろ取物を乾燥し、下記物性値を有する本発明化合物（６２ｍｇ）を得た。
ＴＬＣ：Ｒｆ ０．４７（塩化メチレン：メタノール＝９：１）；
¹Ｈ－ＮＭＲ（ＤＭＳＯ－ｄ₆）：δ 1.70, 3.20, 6.35, 7.59-7.64, 7.67-7.72, 8.41-8.48, 9.92。Reference Example 4: 6-amino-9-tert-butyl-2-{[2-fluoro-4- (methylsulfonyl) phenyl] amino} -7,9-dihydro-8H-purine-8-one

Under a nitrogen atmosphere, the compound (163 mg) prepared in Reference Example 3 was dissolved in ethanol (1.1 mL) and tetrahydrofuran (0.3 mL), and 20% palladium hydroxide carbon (80 mg) was added. The reaction mixture was stirred at 60 ° C. for 6 hours under a hydrogen atmosphere, filtered through Celite (trade name), and the Celite was washed with methylene chloride / methanol. The filtrate was concentrated under reduced pressure. The obtained residue was solidified with ethyl acetate, and the solid was collected by filtration. The filtrate was dried to obtain a compound of the present invention (62 mg) having the following physical characteristics.
TLC: Rf 0.47 (methylene chloride: methanol = 9: 1);
^{1 1} H-NMR (DMSO-d ₆ ): δ 1.70, 3.20, 6.35, 7.59-7.64, 7.67-7.72, 8.41-8.48, 9.92.

４－ブロモ－７－フルオロ－１Ｈ－インダゾール(９１８ｍｇ)の塩化メチレン(１４ｍＬ)溶液に、３，４－ジヒドロ－２Ｈ－ピラン(１．５６ｍＬ)およびパラトルエンスルホン酸・１水和物(８１ｍｇ)を加えた。反応混合物を４０℃で１．５時間撹拌した。反応混合物に飽和炭酸水素ナトリウム水溶液を加え、酢酸エチルで抽出した。得られた有機層を飽和食塩水で洗浄し、無水硫酸ナトリウムで乾燥後、減圧留去した。得られた残渣をシリカゲルカラムクロマトグラフィーで精製することにより、下記物性値を有する標題化合物（１．２４ｇ）を得た。
ＴＬＣ：Ｒｆ ０．６１（ヘキサン：酢酸エチル＝５：１）；
¹Ｈ－ＮＭＲ（ＣＤＣｌ₃）：δ 1.48-1.82, 2.03-2.23, 2.51-2.68, 3.69-3.80, 4.00-4.08, 5.83-5.90, 6.91-7.00, 7.17-7.23, 8.03-8.06。Reference Example 5: 4-bromo-7-fluoro-1- (tetrahydro-2H-pyran-2-yl) -1H-indazole

3,4-Dihydro-2H-pyran (1.56 mL) and p-toluenesulfonic acid monohydrate (81 mg) in a methylene chloride (14 mL) solution of 4-bromo-7-fluoro-1H-indazole (918 mg). Was added. The reaction mixture was stirred at 40 ° C. for 1.5 hours. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The obtained organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography to give the title compound (1.24 g) having the following physical characteristics.
TLC: Rf 0.61 (hexane: ethyl acetate = 5: 1);
^{1 1} H-NMR (CDCl ₃ ): δ 1.48-1.82, 2.03-2.23, 2.51-2.68, 3.69-3.80, 4.00-4.08, 5.83-5.90, 6.91-7.00, 7.17-7.23, 8.03-8.06.

窒素雰囲気下、参考例５で製造された化合物（１．２４ｇ）およびトリイソプロピルボレート（３．８ｍＬ）をテトラヒドロフラン（１６．６ｍＬ）に溶解し、－７８℃に冷却した。その溶液にｎ－ブチルリチウム（８．０２ｍＬ、１．５５Ｍ／ヘキサン）を滴下した。反応混合物を－４０℃で１時間撹拌した。反応混合物に水を加え、有機層を０．５Ｎ水酸化ナトリウム水溶液で逆抽出した。得られた水層に酢酸アンモニウム（１．３９ｇ）を加え、室温で３０分間撹拌した。その反応混合物を０℃に冷却した。反応混合物にリン酸二水素ナトリウムを加え、ｐＨを４～５に調整した。析出した固体をろ取した。ろ取物を冷水で洗浄し、乾燥後、下記物性値を有する本発明化合物（７１０ｍｇ）を得た。
ＴＬＣ：Ｒｆ ０．３４（ヘキサン：酢酸エチル＝２：１）；
¹Ｈ－ＮＭＲ（ＤＭＳＯ－ｄ₆）：δ 1.47-1.60, 1.63-1.82, 1.97-2.10, 2.35-2.54, 3.58-3.69, 3.83-3.94, 5.79-5.85, 7.18-7.27, 7.58-7.64, 8.27, 8.34-8.37。Reference Example 6: [7-Fluoro-1- (tetrahydro-2H-pyran-2-yl) -1H-indazole-4-yl] boronic acid

Under a nitrogen atmosphere, the compound (1.24 g) and triisopropyl borate (3.8 mL) prepared in Reference Example 5 were dissolved in tetrahydrofuran (16.6 mL) and cooled to −78 ° C. N-Butyllithium (8.02 mL, 1.55 M / hexane) was added dropwise to the solution. The reaction mixture was stirred at −40 ° C. for 1 hour. Water was added to the reaction mixture, and the organic layer was back-extracted with 0.5N aqueous sodium hydroxide solution. Ammonium acetate (1.39 g) was added to the obtained aqueous layer, and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was cooled to 0 ° C. Sodium dihydrogen phosphate was added to the reaction mixture to adjust the pH to 4-5. The precipitated solid was collected by filtration. The filtrate was washed with cold water and dried to obtain the compound of the present invention (710 mg) having the following physical characteristics.
TLC: Rf 0.34 (hexane: ethyl acetate = 2: 1);
^{1 1} H-NMR (DMSO-d ₆ ): δ 1.47-1.60, 1.63-1.82, 1.97-2.10, 2.35-2.54, 3.58-3.69, 3.83-3.94, 5.79-5.85, 7.18-7.27, 7.58-7.64, 8.27, 8.34-8.37.

参考例４で製造された化合物（４５ｍｇ）、参考例６で製造された化合物（６０ｍｇ）、酢酸銅（Ｃｕ（ＯＡｃ）₂）（４１ｍｇ）、およびトリエチルアミン（６４μＬ）のアセトニトリル（０．５７ｍＬ）溶液を４０℃で２０時間撹拌した。反応混合物にアンモニア水を加え、酢酸エチルで抽出した。得られた有機層を飽和食塩水で洗浄し、硫酸ナトリウムにて乾燥後、減圧濃縮した。得られた残渣をシリカゲルカラムクロマトグラフィーで精製することにより、下記物性値を有する標題化合物（１９ｍｇ）を得た。
ＴＬＣ：Ｒｆ ０．５３（ヘキサン：酢酸エチル＝１：２）；
¹Ｈ－ＮＭＲ（ＣＤＣｌ₃）：δ 1.55-1.84, 1.89, 2.04-2.24, 2.48-2.69, 3.06, 3.69-3.86, 3.97-4.16, 4.18-4.29, 5.88-5.97, 7.03-7.12, 7.16-7.27, 7.62-7.74, 7.92-8.01, 8.73-8.80。Reference Example 7: 6-amino-9-tert-butyl-2-{[2-fluoro-4- (methylsulfonyl) phenyl] amino} -7- [7-fluoro-1- (tetrahydro-2H-pyran-2) -Il) -1H-Indazole-4-Il] -7,9-Dihydro-8H-Prince-8-on

A solution of the compound prepared in Reference Example 4 (45 mg), the compound prepared in Reference Example 6 (60 mg), copper acetate (Cu (OAc) ₂ ) (41 mg), and triethylamine (64 μL) in acetonitrile (0.57 mL). Was stirred at 40 ° C. for 20 hours. Ammonia water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The obtained organic layer was washed with saturated brine, dried over sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography to give the title compound (19 mg) having the following physical characteristics.
TLC: Rf 0.53 (hexane: ethyl acetate = 1: 2);
^{1 1} H-NMR (CDCl ₃ ): δ 1.55-1.84, 1.89, 2.04-2.24, 2.48-2.69, 3.06, 3.69-3.86, 3.97-4.16, 4.18-4.29, 5.88-5.97, 7.03-7.12, 7.16-7.27, 7.62-7.74, 7.92-8.01, 8.73-8.80.

参考例７で製造された化合物（４０ｍｇ）をメタノール（０．５ｍＬ）に溶解した。その溶液に４Ｎ塩酸／ジオキサン（１ｍＬ）を室温で加えた。反応混合物を室温で１時間撹拌した後、飽和炭酸水素ナトリウム水溶液を加えた。反応混合物を酢酸エチルで抽出した。得られた有機層を飽和食塩水で洗浄し、硫酸ナトリウムにて乾燥後、減圧濃縮した。得られた残渣をヘキサンで洗浄し、ろ取した。ろ取物を乾燥することにより、下記物性値を有する本発明化合物（１０ｍｇ）を得た。
ＴＬＣ：Ｒｆ ０．５８（ヘキサン：酢酸エチル＝１：２）；
¹Ｈ－ＮＭＲ（ＣＤＣｌ₃）：δ 1.91, 3.07, 4.24, 7.07-7.12, 7.17-7.24, 7.63-7.76, 8.02-8.05, 8.73-8.81。Example 1: 6-amino-7- (7-fluoro-1H-indazole-4-yl) -2-{[2-fluoro-4- (methylsulfonyl) phenyl] amino} -9- (2-methyl-) 2-Propanil) -7,9-dihydro-8H-purine-8-on

The compound (40 mg) prepared in Reference Example 7 was dissolved in methanol (0.5 mL). 4N hydrochloric acid / dioxane (1 mL) was added to the solution at room temperature. The reaction mixture was stirred at room temperature for 1 hour, and then saturated aqueous sodium hydrogen carbonate solution was added. The reaction mixture was extracted with ethyl acetate. The obtained organic layer was washed with saturated brine, dried over sodium sulfate, and concentrated under reduced pressure. The obtained residue was washed with hexane and collected by filtration. By drying the filtrate, the compound of the present invention (10 mg) having the following physical characteristics was obtained.
TLC: Rf 0.58 (hexane: ethyl acetate = 1: 2);
^{1 1} H-NMR (CDCl ₃ ): δ 1.91, 3.07, 4.24, 7.07-7.12, 7.17-7.24, 7.63-7.76, 8.02-8.05, 8.73-8.81.

Example 2
Reference Example 1 → Reference Example 2 → Reference Example 3 → Reference Example 4 → Reference Example 7 using isopropylamine instead of tert-butylamine and corresponding boronic acid instead of the compound produced in Reference Example 6. → The same operation as in Example 1 was carried out to obtain a compound of the present invention having the following physical property values.

ＴＬＣ：Ｒｆ ０．３７（ヘキサン：酢酸エチル＝２：３）；
¹Ｈ－ＮＭＲ（ＣＤＣｌ₃）：δ 1.62-1.74, 3.07, 4.35, 4.78-4.88, 7.08-7.14, 7.28-7.35, 7.49-7.54, 7.64-7.80, 8.11, 8.80-8.87。Examples 2-1: 6-amino-7- (7-chloro-1H-indazole-4-yl) -2-{[2-fluoro-4- (methylsulfonyl) phenyl] amino} -9-isopropyl-7 , 9-Dihydro-8H-Purin-8-on

TLC: Rf 0.37 (hexane: ethyl acetate = 2: 3);
^{1 1} H-NMR (CDCl ₃ ): δ 1.62-1.74, 3.07, 4.35, 4.78-4.88, 7.08-7.14, 7.28-7.35, 7.49-7.54, 7.64-7.80, 8.11, 8.80-8.87.

ＴＬＣ：Ｒｆ ０．３０（酢酸エチル）；
¹Ｈ－ＮＭＲ（ＣＤＣｌ₃）：δ 1.60-1.80, 3.07, 4.41, 4.77-4.91, 7.03-7.11, 7.30-7.38, 7.62-7.68, 7.69-7.78, 7.98-8.02, 8.78-8.85。Example 2-2: 6-amino-7- (6,7-difluoro-1H-indazole-4-yl) -2-{[2-fluoro-4- (methylsulfonyl) phenyl] amino} -9-isopropyl -7,9-dihydro-8H-purine-8-on

TLC: Rf 0.30 (ethyl acetate);
^{1 1} H-NMR (CDCl ₃ ): δ 1.60-1.80, 3.07, 4.41, 4.77-4.91, 7.03-7.11, 7.30-7.38, 7.62-7.68, 7.69-7.78, 7.98-8.02, 8.78-8.85.

ＴＬＣ：Ｒｆ ０．４０（ヘキサン：酢酸エチル＝１：４）；
¹Ｈ－ＮＭＲ（ＣＤＣｌ₃）：δ 1.62-1.72, 3.07, 4.33, 4.79-4.92, 7.07-7.14, 7.17-7.25, 7.30-7.35, 7.64-7.69, 7.72-7.78, 8.04-8.08, 8.80-8.88。Example 3: 6-amino-7- (7-fluoro-1H-indazole-4-yl) -2-{[2-fluoro-4- (methylsulfonyl) phenyl] amino} -9-isopropyl-7,9 -Using isopropylamine instead of dihydro-8H-purine-8-on-tert-butylamine, the same operation as in Reference Example 1 → Reference Example 2 → Reference Example 3 → Reference Example 4 → Reference Example 7 → Example 1. The compound of the present invention having the following physical property values was obtained.

TLC: Rf 0.40 (hexane: ethyl acetate = 1: 4);
^{1 1} H-NMR (CDCl ₃ ): δ 1.62-1.72, 3.07, 4.33, 4.79-4.92, 7.07-7.14, 7.17-7.25, 7.30-7.35, 7.64-7.69, 7.72-7.78, 8.04-8.08, 8.80-8.88.

２，４，６－トリクロロ－５－ニトロピリミジン（４ｇ）の塩化メチレン（１３０ｍＬ）溶液に、ビス（４－メトキシベンジル）アミン(４．５ｇ)およびトリエチルアミン（２．４ｍＬ）の塩化メチレン（２０ｍＬ）溶液を０℃でゆっくり滴下した。反応混合物を０℃で３０分間撹拌した。反応混合物にイソプロピルアミン（１．７ｍＬ）およびトリエチルアミン（２．７ｍＬ）の塩化メチレン（２０ｍＬ）溶液を０℃で滴下した。反応混合物を１２０分間撹拌した。反応混合物に水を注ぎ、塩化メチレンで抽出した。得られた有機層を飽和食塩水で洗浄し、硫酸マグネシウムにて乾燥後、減圧濃縮した。得られた残渣をヘキサン／ＭＴＢＥ（４／１）中で３０分撹拌した。析出した固体をろ取した。ろ取物を乾燥することより、以下の物性値を有する標題化合物（７．８ｇ）を得た。
ＴＬＣ：Ｒｆ ０．４１（ヘキサン：酢酸エチル＝５：１）；
¹Ｈ－ＮＭＲ（ＣＤＣｌ₃）：δ 1.24-1.30, 3.80, 4.37-4.50, 6.79-6.85, 6.97-7.03, 8.18-8.24。Reference Example 8: 2-Chloro-N, N-bis (4-methoxybenzyl) -5-nitro-N'-(propane-2-yl) pyrimidine-4,6-diamine

Methylene chloride (20 mL) of bis (4-methoxybenzyl) amine (4.5 g) and triethylamine (2.4 mL) in a solution of 2,4,6-trichloro-5-nitropyrimidine (4 g) in methylene chloride (130 mL). The solution was slowly added dropwise at 0 ° C. The reaction mixture was stirred at 0 ° C. for 30 minutes. A solution of isopropylamine (1.7 mL) and triethylamine (2.7 mL) in methylene chloride (20 mL) was added dropwise to the reaction mixture at 0 ° C. The reaction mixture was stirred for 120 minutes. Water was poured into the reaction mixture and the mixture was extracted with methylene chloride. The obtained organic layer was washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The obtained residue was stirred in hexane / MTBE (4/1) for 30 minutes. The precipitated solid was collected by filtration. By drying the filtrate, the title compound (7.8 g) having the following physical characteristics was obtained.
TLC: Rf 0.41 (hexane: ethyl acetate = 5: 1);
^{1 1} H-NMR (CDCl ₃ ): δ 1.24-1.30, 3.80, 4.37-4.50, 6.79-6.85, 6.97-7.03, 8.18-8.24.

塩化アンモニウム（５．４ｇ）を水（３０ｍＬ）に溶解し、亜鉛（１１ｇ）と混合した。この懸濁液に参考例８で製造された化合物（７．８ｇ）の酢酸エチル（２００ｍＬ）溶液を室温で滴下した。反応混合物を室温で５時間撹拌した。反応混合物をセライト（商品名）にてろ過し、セライトを水および酢酸エチルで洗浄した。得られたろ液を酢酸エチルで抽出した。得られた有機層を水および飽和食塩水で洗浄し、硫酸マグネシウムにて乾燥後、減圧濃縮した。得られた残渣のテトラヒドロフラン（１５０ｍＬ）溶液に、１，１’－カルボニルジイミダゾール(５ｇ)とＤＢＵ（２．３ｍＬ）を加えた。反応混合物を室温で２０時間撹拌した。反応混合物に１Ｎ塩酸を加え、酢酸エチルで抽出した。得られた有機層を１Ｎ塩酸、飽和炭酸水素ナトリウム水溶液および飽和食塩水で洗浄した。得られた有機層を硫酸マグネシウムにて乾燥後、減圧濃縮した。得られた残渣をヘキサン／酢酸エチル（２／１）中で２０分撹拌し、ろ取した。ろ取物を乾燥することより、以下の物性値を有する標題化合物（５．９ｇ）を得た。
ＴＬＣ：Ｒｆ ０．３４（ヘキサン：酢酸エチル＝２：１）；
¹Ｈ－ＮＭＲ（ＣＤＣｌ₃）：δ 1.38-1.48, 3.80, 4.55-4.74, 6.80-6.92, 7.09-7.21, 8.39。Reference Example 9: 2-Chloro-6- [bis (4-methoxybenzyl) amino] -9- (propane-2-yl) -7,9-dihydro-8H-purine-8-one

Ammonium chloride (5.4 g) was dissolved in water (30 mL) and mixed with zinc (11 g). A solution of the compound (7.8 g) prepared in Reference Example 8 in ethyl acetate (200 mL) was added dropwise to this suspension at room temperature. The reaction mixture was stirred at room temperature for 5 hours. The reaction mixture was filtered through Celite (trade name) and the Celite was washed with water and ethyl acetate. The obtained filtrate was extracted with ethyl acetate. The obtained organic layer was washed with water and saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. To a solution of the obtained residue in tetrahydrofuran (150 mL) was added 1,1'-carbonyldiimidazole (5 g) and DBU (2.3 mL). The reaction mixture was stirred at room temperature for 20 hours. 1N Hydrochloric acid was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The obtained organic layer was washed with 1N hydrochloric acid, saturated aqueous sodium hydrogen carbonate solution and saturated brine. The obtained organic layer was dried over magnesium sulfate and then concentrated under reduced pressure. The obtained residue was stirred in hexane / ethyl acetate (2/1) for 20 minutes and collected by filtration. By drying the filtrate, the title compound (5.9 g) having the following physical characteristics was obtained.
TLC: Rf 0.34 (hexane: ethyl acetate = 2: 1);
^{1 1} H-NMR (CDCl ₃ ): δ 1.38-1.48, 3.80, 4.55-4.74, 6.80-6.92, 7.09-7.21, 8.39.

参考例９で製造された化合物（３ｇ）、１－（４－アミノ－３－フルオロフェニル）エタノン（１．１ｇ）および炭酸セシウム（６．３ｇ）のジメトキシエタン（２１ｍＬ）／ｔｅｒｔ-ブタノール（２１ｍＬ）溶液を脱気してアルゴン置換した。この反応混合物に２－（ジシクロヘキシルホスフィノ）－２’，４’，６’－トリイソプロピルビフェニル（３１０ｍｇ）およびトリス（ジベンジリデンアセトン）ジパラジウム（０）（２９０ｍｇ）を加えた。反応混合物を９０℃で４時間撹拌した。さらに２－（ジシクロヘキシルホスフィノ）－２’，４’，６’－トリイソプロピルビフェニル（１５５ｍｇ）およびトリス（ジベンジリデンアセトン）ジパラジウム（０）（１４５ｍｇ）を加えた。反応混合物を９０℃で４時間撹拌した。反応混合物をセライト（商品名）にてろ過した。セライトを酢酸エチルで洗浄した。得られたろ液を減圧濃縮した。得られた残渣をシリカゲルカラムクロマトグラフィーで精製した。得られた粗生成物をＭＴＢＥで洗浄し、ろ取した。ろ取物を乾燥することにより、下記物性値を有する標題化合物（２．４ｇ）を得た。
ＴＬＣ：Ｒｆ ０．２８（ヘキサン：酢酸エチル＝３：２）；
¹Ｈ－ＮＭＲ（ＣＤＣｌ₃）：δ 1.54-1.61, 2.54, 3.81, 4.60-4.78, 6.86-6.93, 7.16-7.26, 7.56-7.61, 7.65-7.71, 8.48-8.56。Reference Example 10: 2-[(4-Acetyl-2-fluorophenyl) amino] -6- [bis (4-methoxybenzyl) amino] -9- (propane-2-yl) -7,9-dihydro-8H -Prince-8-on

The compound (3 g), 1- (4-amino-3-fluorophenyl) etanone (1.1 g) and cesium carbonate (6.3 g) dimethoxyethane (21 mL) / tert-butanol (21 mL) prepared in Reference Example 9 ) The solution was degassed and replaced with argon. 2- (Dicyclohexylphosphino) -2', 4', 6'-triisopropylbiphenyl (310 mg) and tris (dibenzylideneacetone) dipalladium (0) (290 mg) were added to this reaction mixture. The reaction mixture was stirred at 90 ° C. for 4 hours. Further 2- (dicyclohexylphosphino) -2', 4', 6'-triisopropylbiphenyl (155 mg) and tris (dibenzylideneacetone) dipalladium (0) (145 mg) were added. The reaction mixture was stirred at 90 ° C. for 4 hours. The reaction mixture was filtered through Celite (trade name). Celite was washed with ethyl acetate. The obtained filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography. The obtained crude product was washed with MTBE and collected by filtration. By drying the filtrate, the title compound (2.4 g) having the following physical characteristics was obtained.
TLC: Rf 0.28 (hexane: ethyl acetate = 3: 2);
^{1 1} H-NMR (CDCl ₃ ): δ 1.54-1.61, 2.54, 3.81, 4.60-4.78, 6.86-6.93, 7.16-7.26, 7.56-7.61, 7.65-7.71, 8.48-8.56.

参考例１０で製造された化合物（１．７ｇ）を塩化メチレン（５ｍＬ）およびトリフルオロ酢酸（５ｍＬ）に溶解した。反応混合物を６０℃で３時間撹拌した。反応混合物を減圧濃縮した。得られた残渣に飽和炭酸水素ナトリウム水溶液を加えて、酢酸エチル／テトラヒドロフランで抽出した。得られた有機層を飽和食塩水で洗浄し、硫酸マグネシウムにて乾燥後、減圧濃縮した。得られた残渣をヘキサン／酢酸エチル（１／１）で洗浄し、ろ取した。ろ取物を塩化メチレンで洗浄して、ろ取した。ろ取物を乾燥することにより、下記物性値を有する標題化合物（０．５５ｇ）を得た。
ＴＬＣ：Ｒｆ ０．６０（酢酸エチル）；
¹Ｈ－ＮＭＲ（ＤＭＳＯ－ｄ₆）：δ 1.42-1.49, 2.54, 4.42-4.56, 6.36, 7.65-7.78, 8.35-8.40, 8.42-8.51, 9.88。Reference Example 11: 2-[(4-Acetyl-2-fluorophenyl) amino] -6-amino-9- (propane-2-yl) -7,9-dihydro-8H-purine-8-one

The compound (1.7 g) prepared in Reference Example 10 was dissolved in methylene chloride (5 mL) and trifluoroacetic acid (5 mL). The reaction mixture was stirred at 60 ° C. for 3 hours. The reaction mixture was concentrated under reduced pressure. A saturated aqueous sodium hydrogen carbonate solution was added to the obtained residue, and the mixture was extracted with ethyl acetate / tetrahydrofuran. The obtained organic layer was washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The obtained residue was washed with hexane / ethyl acetate (1/1) and collected by filtration. The filtrate was washed with methylene chloride and filtered. By drying the filtrate, the title compound (0.55 g) having the following physical characteristics was obtained.
TLC: Rf 0.60 (ethyl acetate);
^{1 1} H-NMR (DMSO-d ₆ ): δ 1.42-1.49, 2.54, 4.42-4.56, 6.36, 7.65-7.78, 8.35-8.40, 8.42-8.51, 9.88.

参考例４で製造した化合物の代わりに、参考例１１で製造した化合物を用い、参考例６で製造した化合物の代わりに、［１－（テトラヒドロ－２Ｈ－ピラン－２－イル）－１Ｈ－インダゾール－４－イル］ボロン酸を用いて、参考例７→実施例１と同様の操作を行って、以下の物性値を有する本発明化合物を得た。
ＴＬＣ：Ｒｆ ０．２２（ヘキサン：酢酸エチル＝１：４）；
¹Ｈ－ＮＭＲ（ＤＭＳＯ－ｄ₆）：δ 1.53-1.60, 2.53, 4.60-4.72, 5.49, 7.06-7.10, 7.44-7.51, 7.61-7.65, 7.69-7.79, 7.95, 8.44-8.52, 8.60-8.62, 13.32。Example 4: 2-[(4-Acetyl-2-fluorophenyl) amino] -6-amino-7- (1H-indazole-4-yl) -9-isopropyl-7,9-dihydro-8H-purine- 8-on

Instead of the compound produced in Reference Example 4, the compound produced in Reference Example 11 was used, and instead of the compound produced in Reference Example 6, [1- (tetrahydro-2H-pyran-2-yl) -1H-indazole. Using -4-yl] boronic acid, the same operation as in Reference Example 7 → Example 1 was carried out to obtain a compound of the present invention having the following physical property values.
TLC: Rf 0.22 (hexane: ethyl acetate = 1: 4);
^{1 1} H-NMR (DMSO-d ₆ ): δ 1.53-1.60, 2.53, 4.60-4.72, 5.49, 7.06-7.10, 7.44-7.51, 7.61-7.65, 7.69-7.79, 7.95, 8.44-8.52, 8.60-8.62, 13.32.

Example 5
The corresponding amine is used in place of tert-butylamine, the corresponding amine compound is used in place of 2-fluoro-4- (methylsulfonyl) aniline, and the corresponding boronic acid is used in place of the compound prepared in Reference Example 6. In the same operation as in Reference Example 1 → Reference Example 2 → Reference Example 3 → Reference Example 4 → Reference Example 7 → Example 1 to obtain the compound of the present invention having the following physical property values. In Examples 5-1, 5-5, and 5-17, HPLC preparative purification was performed with an eluent containing trifluoroacetic acid (mobile phase (A): 0.1% trifluoroacetic acid aqueous solution; mobile phase (B). ): 0.1% trifluoroacetic acid-acetonitrile), so that the compound of the present invention was obtained as a trifluoroacetic acid salt.

純度（ＬＣ－ＭＳ／ＥＬＳＤ）条件１：７０％（保持時間：０．８５分）；
ＭＡＳＳ（ＥＳＩ，Ｐｏｓ．）：５２３（Ｍ＋Ｈ）⁺；
¹Ｈ－ＮＭＲ（ＤＭＳＯ－ｄ₆）：δ 1.55-1.69, 1.80-2.02, 2.16-2.35, 3.22, 4.71-4.84, 5.53, 7.04-7.09, 7.44-7.51, 7.61-7.66, 7.71-7.76, 7.96, 8.51-8.58, 8.78。Examples 5-1: 6-amino-9-cyclopentyl-2-{[2-fluoro-4- (methylsulfonyl) phenyl] amino} -7- (1H-indazole-4-yl) -7,9-dihydro -8H-Purin-8-one trifluoroacetic acid salt

Purity (LC-MS / ELSD) Condition 1: 70% (retention time: 0.85 minutes);
MASS (ESI, Pos.): 523 (M + H) ⁺ ;
^{1 1} H-NMR (DMSO-d ₆ ): δ 1.55-1.69, 1.80-2.02, 2.16-2.35, 3.22, 4.71-4.84, 5.53, 7.04-7.09, 7.44-7.51, 7.61-7.66, 7.71-7.76, 7.96, 8.51-8.58, 8.78.

Example 5-2: 6-amino-9-cyclobutyl-2-{[2-fluoro-4- (methylsulfonyl) phenyl] amino} -7- (1H-indazole-4-yl) -7,9-dihydro -8H-purine-8-on TLC: Rf 0.26 (hexane: ethyl acetate = 1: 4);
Purity (LC-MS / ELSD) Condition 1: 99.8% (holding time: 0.84 minutes);
MASS (ESI, Pos.): 509 (M + H) ⁺ .

Examples 5-3: 6-amino-2-{[2-fluoro-4- (methylsulfonyl) phenyl] amino} -7- (1H-indazole-4-yl) -9- (2-methyl-2-) Propanil) -7,9-dihydro-8H-purine-8-on TLC: Rf 0.20 (hexane: ethyl acetate = 1: 2);
Purity (LC-MS / ELSD) Condition 1: 97.5% (retention time: 0.85 minutes);
MASS (ESI, Pos.): 511 (M + H) ⁺ ;
^{1 1} H-NMR (CDCl ₃ ): δ 1.92, 3.07, 4.29, 7.15-7.18, 7.23-7.28, 7.46-7.58, 7.63-7.76, 8.02, 8.74-8.82.

Examples 5-4: 6-amino-2-{[2-fluoro-4- (methylsulfonyl) phenyl] amino} -9-isopropyl-7- (7-methyl-1H-indazole-4-yl) -7 , 9-dihydro-8H-purine-8-on TLC: Rf 0.27 (hexane: ethyl acetate = 1: 4);
Purity (LC-MS / ELSD) Condition 1: 99.6% (holding time: 0.83 minutes);
MASS (ESI, Pos.): 511 (M + H) ⁺ ;
^{1 1} H-NMR (CD ₃ OD): δ 1.63-1.70, 2.65, 3.12, 4.77-4.95, 7.08-7.11, 7.30-7.35, 7.65-7.75, 7.96, 8.86-8.94.

純度（ＬＣ－ＭＳ／ＥＬＳＤ）条件１：９９．９％（保持時間：０．８５分）；
ＭＡＳＳ（ＥＳＩ，Ｐｏｓ．）：５５９（Ｍ＋Ｈ）⁺；
¹Ｈ－ＮＭＲ（ＤＭＳＯ－ｄ₆）：δ 2.12-2.23, 2.48-2.58, 2.97-3.12, 3.21, 4.94-5.02, 5.57, 7.08-7.11, 7.47-7.52, 7.62-7.66, 7.73-7.76, 8.00, 8.51-8.54, 8.83, 13.35。Examples 5-5: 6-amino-9- (3,3-difluorocyclopentyl) -2-{[2-fluoro-4- (methylsulfonyl) phenyl] amino} -7- (1H-indazole-4-yl) ) -7,9-Dihydro-8H-purine-8-one trifluoroacetate

Purity (LC-MS / ELSD) Condition 1: 99.9% (holding time: 0.85 minutes);
MASS (ESI, Pos.): 559 (M + H) ⁺ ;
^{1 1} H-NMR (DMSO-d ₆ ): δ 2.12-2.23, 2.48-2.58, 2.97-3.12, 3.21, 4.94-5.02, 5.57, 7.08-7.11, 7.47-7.52, 7.62-7.66, 7.73-7.76, 8.00, 8.51-8.54, 8.83, 13.35.

Examples 5-6: 6-amino-7- (7-chloro-1H-indazole-4-yl) -9-isopropyl-2-{[2-methoxy-4- (methylsulfonyl) phenyl] amino} -7 , 9-dihydro-8H-purine-8-on TLC: Rf 0.25 (ethyl acetate);
Purity (LC-MS / ELSD) Condition 1: 96.5% (retention time: 0.88 minutes);
MASS (ESI, Pos.): 543 (M + H) ⁺ ;
^{1 1} H-NMR (CDCl ₃ ): δ 1.66-1.72, 3.07, 4.01, 4.32, 4.78-4.91, 7.08-7.12, 7.38-7.40, 7.49-7.52, 7.58-7.62, 7.72, 8.11, 8.77-8.80.

純度（ＬＣ－ＭＳ／ＥＬＳＤ）条件１：９９．９％（保持時間：０．８８分）；
ＭＡＳＳ（ＥＳＩ，Ｐｏｓ．）：５４１（Ｍ＋Ｈ）⁺；
¹Ｈ－ＮＭＲ（ＣＤＣｌ₃）：δ 1.92, 3.07, 4.01, 4.22, 7.07-7.12, 7.16-7.23, 7.37-7.39, 7.55-7.60, 7.66, 8.03-8.05, 8.68-8.72。Examples 5-7: 6-amino-7- (7-fluoro-1H-indazole-4-yl) -2-{[2-methoxy-4- (methylsulfonyl) phenyl] amino} -9- (2-) Methyl-2-propanol) -7,9-dihydro-8H-purine-8-one

Purity (LC-MS / ELSD) Condition 1: 99.9% (holding time: 0.88 minutes);
MASS (ESI, Pos.): 541 (M + H) ⁺ ;
^{1 1} H-NMR (CDCl ₃ ): δ 1.92, 3.07, 4.01, 4.22, 7.07-7.12, 7.16-7.23, 7.37-7.39, 7.55-7.60, 7.66, 8.03-8.05, 8.68-8.72.

Examples 5-8: 6-amino-2-{[2-fluoro-4- (methylsulfonyl) phenyl] amino} -7- (1H-indole-6-yl) -9- (tetrahydro-3-franyl) -7,9-dihydro-8H-purine-8-on TLC: Rf 0.57 (ethyl acetate);
^{1 1} H-NMR (CD ₃ OD): δ 2.33-2.45, 2.51-2.63, 3.11, 3.87-3.97, 4.05-4.14, 4.24-4.34, 5.17-5.27, 6.56-6.58, 7.06-7.11, 7.39-7.41, 7.52 -7.54, 7.63-7.75, 8.94-9.01.

純度（ＬＣ－ＭＳ／ＥＬＳＤ）条件１：９９．８％（保持時間：０．８９分）；
ＭＡＳＳ（ＥＳＩ，Ｐｏｓ．）：４９９（Ｍ＋Ｈ）⁺；
¹Ｈ－ＮＭＲ（ＣＤＣｌ₃）：δ 1.69-1.80, 1.99-2.11, 2.31-2.43, 3.07, 4.48, 4.83-4.94, 5.81, 6.87-6.96, 6.97, 7.35-7.40, 7.64-7.74, 8.80-8.85。Examples 5-9: 6-amino-9-cyclopentyl-2-{[2-fluoro-4- (methylsulfonyl) phenyl] amino} -7- (3-hydroxyphenyl) -7,9-dihydro-8H- Pudding-8-on

Purity (LC-MS / ELSD) Condition 1: 99.8% (holding time: 0.89 minutes);
MASS (ESI, Pos.): 499 (M + H) ⁺ ;
^{1 1} H-NMR (CDCl ₃ ): δ 1.69-1.80, 1.99-2.11, 2.31-2.43, 3.07, 4.48, 4.83-4.94, 5.81, 6.87-6.96, 6.97, 7.35-7.40, 7.64-7.74, 8.80-8.85.

Examples 5-10: 6-amino-2-{[2,3-difluoro-4- (methylsulfonyl) phenyl] amino} -7- (7-fluoro-1H-indazole-4-yl) -9-isopropyl -7,9-dihydro-8H-purine-8-on TLC: Rf 0.30 (ethyl acetate);
Purity (LC-MS / ELSD) Condition 1: 97.5% (retention time: 0.86 minutes);
MASS (ESI, Pos.): 533 (M + H) ⁺ ;
^{1 1} H-NMR (CDCl ₃ ): δ 1.64-1.71, 3.23, 4.34, 4.78-4.90, 7.06-7.15, 7.18-7.25, 7.27-7.32, 7.66-7.74, 8.04-8.08, 8.56-8.63.

Examples 5-11: 6-amino-2-{[2,5-difluoro-4- (methylsulfonyl) phenyl] amino} -7- (7-fluoro-1H-indazole-4-yl) -9-isopropyl -7,9-dihydro-8H-purine-8-one purity (LC-MS / ELSD) Condition 1: 99.6% (retention time: 0.86 minutes);
MASS (ESI, Pos.): 533 (M + H) ⁺ ;
^{1 1} H-NMR (CDCl ₃ ): δ 1.64-1.73, 3.23, 4.35, 4.78-4.88, 7.07-7.13, 7.18-7.23, 7.29-7.39, 7.61-7.69, 8.05-8.08, 8.64-8.73, 10.48-10.65.

ＴＬＣ：Ｒｆ ０．５０（ヘキサン：酢酸エチル＝３：７）；
¹Ｈ－ＮＭＲ（ＣＤ₃ＯＤ）：δ 1.57-1.63, 3.11, 4.69-4.82, 6.61-6.69, 6.85-6.91, 7.07-7.16, 7.63-7.73, 8.83-8.92。Examples 5-12: 6-amino-7- (3-amino-4-fluorophenyl) -2-{[2-fluoro-4- (methylsulfonyl) phenyl] amino} -9-isopropyl-7,9- Dihydro-8H-purine-8-on

TLC: Rf 0.50 (hexane: ethyl acetate = 3: 7);
^{1 1} H-NMR (CD ₃ OD): δ 1.57-1.63, 3.11, 4.69-4.82, 6.61-6.69, 6.85-6.91, 7.07-7.16, 7.63-7.73, 8.83-8.92.

ＴＬＣ：Ｒｆ ０．３１（ヘキサン：酢酸エチル＝１：１）；
¹Ｈ－ＮＭＲ（ＣＤＣｌ₃）：δ 1.63-1.72, 3.07, 4.36, 4.76-4.89, 6.83-6.86, 7.24-7.31, 7.34-7.39, 7.61-7.78, 8.81-8.89。Examples 5-13: 6-amino-7- (1-benzofuran-5-yl) -2-{[2-fluoro-4- (methylsulfonyl) phenyl] amino} -9-isopropyl-7,9-dihydro -8H-Purin-8-on

TLC: Rf 0.31 (hexane: ethyl acetate = 1: 1);
^{1 1} H-NMR (CDCl ₃ ): δ 1.63-1.72, 3.07, 4.36, 4.76-4.89, 6.83-6.86, 7.24-7.31, 7.34-7.39, 7.61-7.78, 8.81-8.89.

Examples 5-14: 6-amino-2-{[2-fluoro-4- (methylsulfonyl) phenyl] amino} -7- (1H-indazole-4-yl) -9- (1,1,1-) Trifluoro-2-propanil) -7,9-dihydro-8H-purine-8-on TLC: Rf 0.60 (ethyl acetate);
^{1 1} H-NMR (CD ₃ OD): δ 1.94-2.02, 3.14, 5.20-5.32, 7.20-7.24, 7.55-7.62, 7.66-7.76, 7.96-8.02, 8.83-8.90.

純度（ＬＣ－ＭＳ／ＥＬＳＤ）条件１：１００％（保持時間：０．８６分）；
ＭＡＳＳ（ＥＳＩ，Ｐｏｓ．）：５２９（Ｍ＋Ｈ）⁺；
¹Ｈ－ＮＭＲ（ＣＤＣｌ₃）：δ 0.92-1.01, 1.64-1.69, 1.86-2.02, 2.19-2.37, 3.07, 4.34, 4.50-4.63, 7.08-7.15, 7.18-7.25, 7.28-7.34, 7.62-7.68, 7.70-7.79, 8.00-8.07, 8.79-8.86。Examples 5-15: 6-amino-9-[(2S) -2-butanyl] -7- (7-fluoro-1H-indazole-4-yl) -2-{[2-fluoro-4- (methyl) Sulfonyl) phenyl] amino} -7,9-dihydro-8H-purine-8-on

Purity (LC-MS / ELSD) Condition 1: 100% (holding time: 0.86 minutes);
MASS (ESI, Pos.): 529 (M + H) ⁺ ;
^{1 1} H-NMR (CDCl ₃ ): δ 0.92-1.01, 1.64-1.69, 1.86-2.02, 2.19-2.37, 3.07, 4.34, 4.50-4.63, 7.08-7.15, 7.18-7.25, 7.28-7.34, 7.62-7.68, 7.70-7.79, 8.00-8.07, 8.79-8.86.

ＴＬＣ：Ｒｆ ０．２７（酢酸エチル：メタノール＝３：１）；
¹Ｈ－ＮＭＲ（ＣＤＣｌ₃）：δ 2.10-2.32, 2.42-2.73, 2.81-2.99, 3.08-3.25, 3.43-3.80, 4.49, 4.99-5.12, 6.96-7.00, 7.07-7.18, 7.19-7.40, 7.43-7.51, 8.42-8.50。Examples 5-16: 6-amino-7- (4-chloro-3-hydroxyphenyl) -9- (3,3-difluorocyclopentyl) -2-{[2-fluoro-4- (1-piperazinyl) Carbonyl) phenyl] amino} -7,9-dihydro-8H-purine-8-on

TLC: Rf 0.27 (ethyl acetate: methanol = 3: 1);
^{1 1} H-NMR (CDCl ₃ ): δ 2.10-2.32, 2.42-2.73, 2.81-2.99, 3.08-3.25, 3.43-3.80, 4.49, 4.99-5.12, 6.96-7.00, 7.07-7.18, 7.19-7.40, 7.43- 7.51, 8.42-8.50.

純度（ＬＣ－ＭＳ／ＥＬＳＤ）条件１：１００％（保持時間：０．７８分）；
ＭＡＳＳ（ＥＳＩ，Ｐｏｓ．）：４６９（Ｍ＋Ｈ）⁺；
¹Ｈ－ＮＭＲ（ＤＭＳＯ－ｄ₆）：δ 1.47-1.60, 3.02, 4.38, 4.60-4.70, 5.25-5.50, 6.51-6.55, 7.00-7.04, 7.43-7.50, 7.63-7.68, 7.72-7.79, 8.17, 9.36, 11.35。Examples 5-17: 6-amino-7- (1H-indole-5-yl) -9-isopropyl-2-[(2-methyl-1-oxo-2,3-dihydro-1H-isoindole-5) -Indole) amino] -7,9-dihydro-8H-purine-8-one trifluoroacetate

Purity (LC-MS / ELSD) Condition 1: 100% (retention time: 0.78 minutes);
MASS (ESI, Pos.): 469 (M + H) ⁺ ;
^{1 1} H-NMR (DMSO-d ₆ ): δ 1.47-1.60, 3.02, 4.38, 4.60-4.70, 5.25-5.50, 6.51-6.55, 7.00-7.04, 7.43-7.50, 7.63-7.68, 7.72-7.79, 8.17, 9.36, 11.35.

ＴＬＣ：Ｒｆ ０．２２（酢酸エチル）；
¹Ｈ－ＮＭＲ（ＣＤＣｌ₃）：δ 1.60-1.68, 2.25, 3.84, 4.28, 4.71-4.82, 6.16, 6.58-6.61, 7.09-7.15, 7.29-7.32, 7.54, 7.71-7.75, 7.78, 8.41-8.55。Examples 5-18: 6-amino-2-[(1,3-dimethyl-1H-pyrazole-4-yl) amino] -7- (1H-indole-6-yl) -9-isopropyl-7,9 -Dihydro-8H-Pyrazole-8-on

TLC: Rf 0.22 (ethyl acetate);
^{1 1} H-NMR (CDCl ₃ ): δ 1.60-1.68, 2.25, 3.84, 4.28, 4.71-4.82, 6.16, 6.58-6.61, 7.09-7.15, 7.29-7.32, 7.54, 7.71-7.75, 7.78, 8.41-8.55.

純度（ＬＣ－ＭＳ／ＥＬＳＤ）条件１：９９．８％（保持時間：１．０３分）；
ＭＡＳＳ（ＥＳＩ，Ｐｏｓ．）：４８９（Ｍ＋Ｈ）⁺；
¹Ｈ－ＮＭＲ（ＣＤＣｌ₃）：δ 1.58-1.66, 3.09, 4.71-4.86, 6.52-6.59, 7.02-7.08, 7.20-7.29, 7.38, 7.51-7.58, 7.67-7.73, 8.42-8.50, 9.05。Examples 5-19: 4-{[6-amino-7- (1H-indole-5-yl) -9-isopropyl-8-oxo-8,9-dihydro-7H-purin-2-yl] amino} -3-Fluoro-N, N-dimethylbenzamide

Purity (LC-MS / ELSD) Condition 1: 99.8% (retention time: 1.03 minutes);
MASS (ESI, Pos.): 489 (M + H) ⁺ ;
^{1 1} H-NMR (CDCl ₃ ): δ 1.58-1.66, 3.09, 4.71-4.86, 6.52-6.59, 7.02-7.08, 7.20-7.29, 7.38, 7.51-7.58, 7.67-7.73, 8.42-8.50, 9.05.

純度（ＬＣ－ＭＳ／ＥＬＳＤ）条件１：９７％（保持時間：０．６４分）；
ＭＡＳＳ（ＥＳＩ，Ｐｏｓ．）：５００（Ｍ＋Ｈ）⁺。Examples 5-20: 6-amino-9-cyclopentyl-7- (3-hydroxyphenyl) -2-({4- [2- (1-pyrrolidinyl) ethyl] phenyl} amino) -7,9-dihydro- 8H-Purin-8-on

Purity (LC-MS / ELSD) Condition 1: 97% (retention time: 0.64 minutes);
MASS (ESI, Pos.): 500 (M + H) ⁺ .

Examples 5-21: 4-{[6-amino-9-cyclopentyl-7- (3-hydroxyphenyl) -8-oxo-8,9-dihydro-7H-purin-2-yl] amino} -3- Methoxy-N, N-dimethylbenzamide purity (LC-MS / ELSD) Condition 1: 99.8% (retention time: 0.83 minutes);
MASS (ESI, Pos.): 504 (M + H) ⁺ ;
^{1 1} H-NMR (DMSO-d ₆ ): δ1.61-1.69, 1.86-1.98, 2.15-2.30, 2.98, 3.91, 4.70-4.79, 5.64, 6.78-6.84, 6.95-7.00, 7.05, 7.30-7.35, 7.47 , 8.46-8.49, 9.86.

ＴＬＣ：Ｒｆ ０．３３（酢酸エチル：メタノール＝１：４）；
¹Ｈ－ＮＭＲ（ＣＤ₃ＯＤ）：δ 1.58-1.67, 2.33, 2.56-2.63, 3.49-3.57, 4.68-4.80, 6.78-6.84, 6.94, 7.41-7.47, 7.60-7.71, 7.75-7.84, 8.60-8.68。Examples 5-22: 4-{[6-amino-7- (4-chloro-3-hydroxyphenyl) -9-isopropyl-8-oxo-8,9-dihydro-7H-purin-2-yl] amino } -N- [2- (dimethylamino) ethyl] -3-fluorobenzamide

TLC: Rf 0.33 (ethyl acetate: methanol = 1: 4);
^{1 1} H-NMR (CD ₃ OD): δ 1.58-1.67, 2.33, 2.56-2.63, 3.49-3.57, 4.68-4.80, 6.78-6.84, 6.94, 7.41-7.47, 7.60-7.71, 7.75-7.84, 8.60-8.68 ..

Examples 5-23: 6-amino-9-cyclopentyl-2-{[2-fluoro-4- (4-morpholinylcarbonyl) phenyl] amino} -7- (3-hydroxyphenyl) -7,9- Dihydro-8H-purine-8-one purity (LC-MS / ELSD) Condition 1: 99.4% (retention time: 0.84 minutes);
MASS (ESI, Pos.): 534 (M + H) ⁺ ;
^{1 1} H-NMR (CDCl ₃ ): δ 1.67-1.77, 1.96-2.09, 2.30-2.42, 3.59-3.78, 4.45, 4.82-4.95, 6.23, 6.85-6.94, 7.08, 7.19-7.24, 7.34-7.39, 8.54- 8.61.

Examples 5-24: 4-{[6-amino-9-cyclopentyl-7- (3-hydroxyphenyl) -8-oxo-8,9-dihydro-7H-purin-2-yl] amino} benzamide purity ( LC-MS / ELSD) Condition 1: 99.7% (holding time: 0.93 minutes);
MASS (ESI, Pos.): 446 (M + H) ⁺ ;
^{1 1} H-NMR (DMSO-d ₆ ): δ 1.65-1.75, 1.90-2.10, 2.23-2.38, 4.72-4.85, 5.54, 6.80-6.95, 7.09, 7.31-7.38, 7.71-7.95, 9.27, 9.89.

純度（ＬＣ－ＭＳ／ＥＬＳＤ）条件１：９９％（保持時間：０．７５分）；
ＭＡＳＳ（ＥＳＩ，Ｐｏｓ．）：４８８（Ｍ＋Ｈ）⁺。Examples 5-25: 6-amino-9-cyclopentyl-7- (3-hydroxyphenyl) -2-{[4- (4-morpholinyl) phenyl] amino} -7,9-dihydro-8H-purine-8 -on

Purity (LC-MS / ELSD) Condition 1: 99% (retention time: 0.75 minutes);
MASS (ESI, Pos.): 488 (M + H) ⁺ .

純度（ＬＣ－ＭＳ／ＥＬＳＤ）条件１：９９．８％（保持時間：０．７７分）；
ＭＡＳＳ（ＥＳＩ，Ｐｏｓ．）：５０８（Ｍ＋Ｈ）⁺；
¹Ｈ－ＮＭＲ（ＤＭＳＯ－ｄ₆）：δ 1.65-1.66, 1.83-1.96, 2.16-2.28, 3.24-3.36, 3.47-3.55, 4.69-4.78, 5.55, 6.78-6.87, 7.29-7.34, 7.64-7.72, 8.25-8.30, 8.35-8.41, 9.91。Examples 5-26: 4-{[6-amino-9-cyclopentyl-7- (3-hydroxyphenyl) -8-oxo-8,9-dihydro-7H-purin-2-yl] amino} -3- Fluoro-N- (2-hydroxyethyl) benzamide

Purity (LC-MS / ELSD) Condition 1: 99.8% (retention time: 0.77 minutes);
MASS (ESI, Pos.): 508 (M + H) ⁺ ;
^{1 1} H-NMR (DMSO-d ₆ ): δ 1.65-1.66, 1.83-1.96, 2.16-2.28, 3.24-3.36, 3.47-3.55, 4.69-4.78, 5.55, 6.78-6.87, 7.29-7.34, 7.64-7.72, 8.25-8.30, 8.35-8.41, 9.91.

Examples 5-27: 6-amino-2- ({2-fluoro-4-[(4-hydroxy-1-piperidinyl) carbonyl] phenyl} amino) -7- (1H-indole-5-yl) -9- (Tetrahydro-3-furanyl) -7,9-dihydro-8H-purine-8-one purity (LC-MS / ELSD) Condition 1: 99.9% (retention time: 0.67 minutes);
MASS (ESI, Pos.): 573 (M + H) ⁺ ;
^{1 1} H-NMR (DMSO-d ₆ ): δ 1.32-1.42, 1.72-1.81, 2.18-2.27, 3.16-3.23, 3.72-3.85, 3.93-4.07, 4.77, 4.96-5.04, 5.28, 6.53, 7.12-7.15, 7.21-7.25, 7.48-7.55, 7.64, 8.11-8.18, 8.36, 11.39.

純度（ＬＣ－ＭＳ／ＥＬＳＤ）条件２：１００％（保持時間：０．７２分）；
ＭＡＳＳ（ＥＳＩ，Ｐｏｓ．）：４７２（Ｍ＋Ｈ）⁺。Examples 5-28: 5-{[6-amino-7- (1H-indole-5-yl) -9-isopropyl-8-oxo-8,9-dihydro-7H-purin-2-yl] amino} -N, N-dimethyl-2-pyridinecarboxamide

Purity (LC-MS / ELSD) Condition 2: 100% (retention time: 0.72 minutes);
MASS (ESI, Pos.): 472 (M + H) ⁺ .

純度（ＬＣ－ＭＳ／ＥＬＳＤ）条件２：１００％（保持時間：０．８９分）；
ＭＡＳＳ（ＥＳＩ，Ｐｏｓ．）：４８２（Ｍ＋Ｈ）⁺。Examples 5-29: 6-amino-7- (1H-indole-5-yl) -9-isopropyl-2-[(2-methyl-4-oxo-4H-chromen-7-yl) amino] -7 , 9-Dihydro-8H-Purin-8-on

Purity (LC-MS / ELSD) Condition 2: 100% (retention time: 0.89 minutes);
MASS (ESI, Pos.): 482 (M + H) ⁺ .

純度（ＬＣ－ＭＳ／ＥＬＳＤ）条件２：９９％（保持時間：０．８７分）；
ＭＡＳＳ（ＥＳＩ，Ｐｏｓ．）：４５６（Ｍ＋Ｈ）⁺。Examples 5-30: 6-amino-7- (1H-indole-5-yl) -9-isopropyl-2-[(1-oxo-1,3-dihydro-2-benzofuran-5-yl) amino] -7,9-dihydro-8H-purine-8-on

Purity (LC-MS / ELSD) Condition 2: 99% (retention time: 0.87 minutes);
MASS (ESI, Pos.): 456 (M + H) ⁺ .

純度（ＬＣ－ＭＳ／ＥＬＳＤ）条件１：１００％（保持時間：０．８１分）；
ＭＡＳＳ（ＥＳＩ，Ｐｏｓ．）：４８５（Ｍ＋Ｈ）⁺。Examples 5-31: 7-{[6-amino-7- (1H-indole-5-yl) -9-isopropyl-8-oxo-8,9-dihydro-7H-purin-2-yl] amino} -4-Methyl-2H-1,4-Benzoxazine-3 (4H) -on

Purity (LC-MS / ELSD) Condition 1: 100% (retention time: 0.81 minutes);
MASS (ESI, Pos.): 485 (M + H) ⁺ .

純度（ＬＣ－ＭＳ／ＥＬＳＤ）条件１：９９％（保持時間：０．７２分）；
ＭＡＳＳ（ＥＳＩ，Ｐｏｓ．）：５２５（Ｍ＋Ｈ）⁺；
¹Ｈ－ＮＭＲ（ＤＭＳＯ－ｄ₆）：δ 2.20-2.29, 2.45-2.55, 3.82-3.89, 3.99-4.03, 4.08-4.12, 4.99-5.07, 5.34, 6.53, 7.12-7.15, 7.32, 7.48-7.59, 7.65, 8.42-8.47, 8.50, 11.40。Examples 5-32: 4-{[6-amino-7- (1H-indole-5-yl) -8-oxo-9- (tetrahydro-3-franyl) -8,9-dihydro-7H-purine- 2-Indole] Amino} -3-Fluorobenzene Sulfonamide

Purity (LC-MS / ELSD) Condition 1: 99% (holding time: 0.72 minutes);
MASS (ESI, Pos.): 525 (M + H) ⁺ ;
^{1 1} H-NMR (DMSO-d ₆ ): δ 2.20-2.29, 2.45-2.55, 3.82-3.89, 3.99-4.03, 4.08-4.12, 4.99-5.07, 5.34, 6.53, 7.12-7.15, 7.32, 7.48-7.59, 7.65, 8.42-8.47, 8.50, 11.40.

Pharmacological experiment example:
Pharmacological Experiment Example 1: Measurement of Brk Inhibitory Activity Measurement of Brk enzyme inhibitory activity was carried out by LanthaScreen (registered trademark) system (Invitrogen) according to the attached instruction manual. The reagents used are shown below.
Reaction buffer: A solution containing 50 mmol / L HEPES (pH 7.5), 0.01% Brij35, 10 mmol / L MgCl ₂ and 1 mmol / L EGTA was prepared using purified water.
Test substance (compound of the present invention) solution: A DMSO solution of each concentration of the test compound was diluted 20-fold with a reaction buffer to prepare a solution containing the test compound having a concentration of 5 times the final concentration.
Enzyme solution: A solution containing 480 ng / mL Brk enzyme was prepared using a reaction buffer.
Substrate solution: A solution containing 57 μmol / L ATP and 500 nmol / L Fluorescein-Poly GT (Invitrogen) was prepared using a reaction buffer.
Detection solution: A solution containing 20 mmol / L EDTA and 4 nmol / L PY20 (Invitrogen) was prepared using Dilution B (Invitrogen).

Ａ：ブランク群のＴＲ－ＦＲＥＴ比の平均値
Ｂ：媒体群のＴＲ－ＦＲＥＴ比の平均値A DMSO solution of the test compound at 10 mmol / L was dispensed into a 96-well plate (Nunc), and a dilution series having a 3-fold common ratio was further prepared by DMSO. To each well of the 96-well plate for measurement, a reaction buffer containing DMSO was added to the blank group and the medium group, and 5 μL of the test substance solution was added to the test substance group. Next, 10 μL of each well of the reaction buffer was added to the blank group, and 10 μL of each well was added to the medium group and the test compound group, and the mixture was stirred at room temperature for 10 minutes. After completion of stirring, 10 μL of the substrate solution was added to each well, and the mixture was stirred at room temperature and in the dark for 1 hour. After completion of the reaction, 25 μL of the detection solution was added to each well, and the mixture was allowed to stand at room temperature and in the dark for 30 minutes. After standing, the fluorescence intensities at 520 nm and 495 nm when irradiated with excitation light of 340 nm using Analyst GT (Molecular Devices) were measured, and the phosphorylation of the artificial substrate was measured by time-resolved fluorescence resonance energy transfer (TR-FRET). Quantified. The TR-FRET ratio was calculated by dividing the 520 nm fluorescence signal by the 495 nm fluorescence signal for each well, and the inhibition rate (%) in the test compound group was calculated by the following formula 1.

A: Mean value of TR-FRET ratio of blank group B: Mean value of TR-FRET ratio of medium group

The value of the 50% inhibition rate (IC ₅₀ value) of the test compound was calculated from the inhibition curve based on the inhibition rate at each concentration of the test compound.

As a result, it was found that the IC ₅₀ value of the compound of the present invention was 0.1 μmol / L or less, and the compound of the present invention had a strong Brk inhibitory activity. For example, the _IC50 values of some of the compounds of the invention were as shown in Table 1 below.

Pharmacological experiment example 2: Enzyme inhibitory activity test against kinases other than Brk (selectivity experiment)
The compound of the present invention was dissolved in DMSO to prepare a solution having a concentration 100 times the test concentration of 1 μmol / L. The solution was further diluted 25-fold with assay buffer (20 mmol / L HEPES, 0.01% Triton X-100, 2 mmol / L DTT, pH 7.5) to obtain a test substance solution. For the positive control substance, a positive control substance solution was prepared in the same manner.

A 5 μL 4-fold test substance solution prepared in the assay buffer, a 5 μL 4-fold substrate / ATP / metal solution (Mg) and a 10 μL 2-fold kinase solution were mixed in the wells of a polypropylene 384-well plate. The reaction was carried out at room temperature for 1 hour. 60 μL of Termination Buffer (QuickScreen Screening Assist MSA; Carna Biosciences) was added to terminate the reaction. Substrate peptides and phosphorylated peptides in the reaction solution were separated and quantified. The kinase reaction was evaluated by the product ratio (P / (P + S)) calculated from the substrate peptide peak height (S) and the phosphorylated peptide peak height (P). Kinase selectivity experiments were performed using, for example, p38α and Syk kinases as other kinases. Table 2 below shows the substrate, substrate concentration, ATP concentration, and positive control substances used for each kinase enzyme inhibitory activity test.

The mean signal of the control well containing all the reaction components was 0% inhibition, the mean signal of the background well (without enzyme addition) was 100% inhibition, and the inhibition rate was calculated from the mean signal of each test substance test well. For example, the inhibition rates of the compounds of the present invention in Examples 3 and 4 at a concentration of 1 μmol / L for each kinase are as shown in Table 3 below.

It was found that the compound of the present invention has a strong inhibitory activity against Brk and has excellent kinase selectivity. For example, as shown in Table 3 above, Examples 3 and 4 of the compounds of the present invention have 24% or less inhibition (1 μmol / L compound concentration) against the kinases of p38α and Syk. On the other hand, the IC _50s having an inhibitory activity against Brk were 0.005 μmol / L and 0.011 μmol / L, respectively (from Pharmacological Experimental Example 1).

[Example of pharmaceutical product]
By mixing each of the following components by a conventional method and then tableting, 10,000 tablets containing 10 mg of the active ingredient in one tablet can be obtained.
2-[(4-Acetyl-2-fluorophenyl) amino] -6-amino-7- (1H-indazole-4-yl) -9-isopropyl-7,9-dihydro-8H-purine-8-one ...... 100g
・ Carboxymethyl cellulose calcium (disintegrant) …… 20g
・ Magnesium stearate (lubricant) …… 10g
・ Microcrystalline cellulose …… 870g

The compound of the present invention has Brk inhibitory activity and is effective for treating diseases in which Brk is involved, for example, diseases such as cancer.

Claims (16)

General formula (I)

(During the ceremony,
ring1 and ring2 independently represent a C5-10 carbocycle or a 5-10-membered heterocycle, respectively.
R ¹ represents C1-4 alkyl, C2-4 alkenyl, C2-4 alkynyl, C3-6 cycloalkyl, or 3-6 member heterocycloalkyl, the C1-4 alkyl, C2-4 alkenyl, C2-4. The alkynyl, C3-6 cycloalkyl, or 3-6 member heterocycloalkyl may be substituted with 1-5 halogens or hydroxyl groups.
R ² represents halogen, C1-4 alkyl, OR ⁴ , NR ⁵ R ⁶ , or oxo, the C1-4 alkyl may be substituted with 1-5 halogens.
R ⁴ represents a hydrogen atom, C1-4 alkyl, or benzene ring, and the C1-4 alkyl or benzene ring may be substituted with 1 to 5 halogens.
R ⁵ and R ⁶ independently represent a hydrogen atom or C1-4 alkyl, respectively.
R ³ represents a halogen, C1-4 alkyl, OR ⁷ , NR ⁸ R ⁹ , SO ₂ R ¹⁰ , COR ¹¹ , benzene ring, 4-6 membered heterocycle, or oxo, the C1-4 alkyl representing a halogen. , A hydroxyl group, a 4-6 membered heterocycle, and may be substituted with 1-5 substituents selected from the group consisting of CONR ¹² R ¹³ .
R ⁷ represents a hydrogen atom or C1-4 alkyl, which C1-4 alkyl may be substituted with 1-5 halogens or NR ¹⁴ R ¹⁵ .
R ⁸ and R ⁹ independently represent a hydrogen atom, C1-4 alkyl, or acetyl, respectively.
R ¹⁰ represents C1-4 alkyl or NR ¹⁶ R ¹⁷
R ¹¹ represents a hydroxyl group, C1-4 alkyl, NR ¹⁸ R ¹⁹ , or a 4-6 membered heterocycle, the 4-6 membered heterocycle being selected from the group consisting of halogens, hydroxyl groups, and C1-4 alkyl. It may be substituted with 1 to 5 substituents.
R ¹² , R ¹³ , R ¹⁴ , R ¹⁵ , R ¹⁶ and R ¹⁷ independently represent a hydrogen atom or C1-4 alkyl, respectively.
R ¹⁸ and R ¹⁹ each independently represent a hydrogen atom, a C1-4 alkyl, or a 4-6 membered heterocycle, the C1-4 alkyl being 1-5 hydroxyls, C1-3 alkoxy, or. It may be replaced with NR ²⁰ R ²¹ .
R ²⁰ and R ²¹ independently represent a hydrogen atom or C1-4 alkyl, respectively.
p represents an integer from 0 to 7.
q represents an integer from 0 to 7.
However, when p and q each represent an integer of 2 or more, R ² and R ³ may be the same or different, respectively. )
A compound represented by, a salt thereof, an N-oxide compound thereof, or a solvate thereof. The compound according to claim 1, wherein R ¹ is isopropyl, tert-butyl, isobutyl, C3-6 cycloalkyl, or 3-6 member heterocycloalkyl, optionally substituted with 1-5 halogens or hydroxyl groups. , The salt, the N-oxide, or the solvate thereof. The compound according to claim 1 or 2, wherein ring1 is a 9-10-membered nitrogen-containing bicyclic aromatic heterocycle, a salt thereof, an N-oxide compound thereof, or a solvate thereof. The compound according to any one of claims 1 to 3, wherein ring2 is a benzene ring, a salt thereof, an N-oxide compound thereof, or a solvate thereof. The compound according to any one of claims 1 to 4, wherein q is 1 or more and at least one R ³ is halogen, C1-3 alkoxy, SO ₂ R ¹⁰ , or COR ¹¹ . A salt, its N-oxide, or a solvate thereof. General formula (I-1)

(In the formula, ring1-1 represents an indole ring or an indazole ring, R ^1-1 represents isopropyl, tert-butyl, cyclobutyl, cyclopentyl, difluorocyclopentyl, oxetanyl, or tetrahydrofuranyl, X represents halogen, p- 1 represents an integer of 0 to 6, q-1 represents an integer of 0 to 4, and other symbols have the same meanings as the symbols described in claim 1.)
The compound according to claim 1, a salt thereof, an N-oxide compound thereof, or a solvate thereof. General formula (I-1')

(In the formula, R ^3'represents SO ₂ R ¹⁰ or COR ¹¹ , and the other symbols have the same meanings as those described in claim 1 or 6.)
The compound according to claim 1, a salt thereof, an N-oxide compound thereof, or a solvate thereof. (1) 6-Amino-7- (7-fluoro-1H-indazole-4-yl) -2-{[2-fluoro-4- (methylsulfonyl) phenyl] amino} -9-isopropyl-7,9- Dihydro-8H-purine-8-on,
(2) 6-Amino-7- (7-chloro-1H-indazole-4-yl) -2-{[2-fluoro-4- (methylsulfonyl) phenyl] amino} -9-isopropyl-7,9- Dihydro-8H-purine-8-on,
(3) 6-Amino-7- (6,7-difluoro-1H-indazole-4-yl) -2-{[2-fluoro-4- (methylsulfonyl) phenyl] amino} -9-isopropyl-7, 9-Dihydro-8H-Purin-8-on,
(4) 6-Amino-7- (7-fluoro-1H-indazole-4-yl) -2-{[2-fluoro-4- (methylsulfonyl) phenyl] amino} -9- (2-methyl-2) -Propanil) -7,9-dihydro-8H-purine-8-on,
(5) 2-[(4-Acetyl-2-fluorophenyl) amino] -6-amino-7- (1H-indazole-4-yl) -9-isopropyl-7,9-dihydro-8H-purine-8 -on,
(6) 6-Amino-9-Cyclopentyl-2-{[2-fluoro-4- (methylsulfonyl) phenyl] amino} -7- (1H-indazole-4-yl) -7,9-dihydro-8H- Pudding-8-on,
(7) 6-Amino-9-Cyclobutyl-2-{[2-fluoro-4- (methylsulfonyl) phenyl] amino} -7- (1H-indazole-4-yl) -7,9-dihydro-8H- Pudding-8-on,
(8) 6-Amino-2-{[2-fluoro-4- (methylsulfonyl) phenyl] amino} -7- (1H-indazole-4-yl) -9- (2-methyl-2-propanol)- 7,9-dihydro-8H-purine-8-on,
(9) 6-Amino-2-{[2-fluoro-4- (methylsulfonyl) phenyl] amino} -9-isopropyl-7- (7-methyl-1H-indazole-4-yl) -7,9- Dihydro-8H-purine-8-on,
(10) 6-Amino-9- (3,3-difluorocyclopentyl) -2-{[2-fluoro-4- (methylsulfonyl) phenyl] amino} -7- (1H-indazole-4-yl) -7 , 9-dihydro-8H-purine-8-on,
(11) 6-Amino-7- (7-chloro-1H-indazole-4-yl) -9-isopropyl-2-{[2-methoxy-4- (methylsulfonyl) phenyl] amino} -7,9- Dihydro-8H-purine-8-on,
(12) 6-Amino-7- (7-Fluoro-1H-Indazole-4-yl) -2-{[2-Methoxy-4- (methylsulfonyl) phenyl] amino} -9- (2-Methyl-2) -Propanil) -7,9-dihydro-8H-purine-8-on,
(13) 6-Amino-2-{[2-fluoro-4- (methylsulfonyl) phenyl] amino} -7- (1H-indole-6-yl) -9- (tetrahydro-3-furanyl) -7, 9-Dihydro-8H-Purin-8-on,
(14) 6-Amino-9-Cyclopentyl-2-{[2-fluoro-4- (methylsulfonyl) phenyl] amino} -7- (3-hydroxyphenyl) -7,9-dihydro-8H-purine-8 -on,
(15) 6-Amino-2-{[2,3-difluoro-4- (methylsulfonyl) phenyl] amino} -7- (7-fluoro-1H-indazole-4-yl) -9-isopropyl-7, 9-Dihydro-8H-Purin-8-on,
(16) 6-Amino-2-{[2,5-difluoro-4- (methylsulfonyl) phenyl] amino} -7- (7-fluoro-1H-indazole-4-yl) -9-isopropyl-7, 9-Dihydro-8H-Purin-8-on,
(17) 6-Amino-7- (3-amino-4-fluorophenyl) -2-{[2-fluoro-4- (methylsulfonyl) phenyl] amino} -9-isopropyl-7,9-dihydro-8H -Prince-8-on,
(18) 6-Amino-7- (1-benzofuran-5-yl) -2-{[2-fluoro-4- (methylsulfonyl) phenyl] amino} -9-isopropyl-7,9-dihydro-8H- Pudding-8-on,
(19) 6-Amino-2-{[2-fluoro-4- (methylsulfonyl) phenyl] amino} -7- (1H-indazole-4-yl) -9- (1,1,1-trifluoro-) 2-Propanil) -7,9-dihydro-8H-purine-8-on,
(20) 6-Amino-9-[(2S) -2-butanyl] -7- (7-fluoro-1H-indazole-4-yl) -2-{[2-fluoro-4- (methylsulfonyl) phenyl ] Amino} -7,9-dihydro-8H-purine-8-on,
(21) 6-Amino-7- (4-chloro-3-hydroxyphenyl) -9- (3,3-difluorocyclopentyl) -2-{[2-fluoro-4- (1-piperazinylcarbonyl) phenyl ] Amino} -7,9-dihydro-8H-purine-8-on,
(22) 6-Amino-7- (1H-indole-5-yl) -9-isopropyl-2-[(2-Methyl-1-oxo-2,3-dihydro-1H-isoindole-5-yl) Amino] -7,9-dihydro-8H-purine-8-on,
(23) 6-Amino-2-[(1,3-dimethyl-1H-pyrazole-4-yl) amino] -7- (1H-indole-6-yl) -9-isopropyl-7,9-dihydro- 8H-Pyrazole-8-On,
(24) 4-{[6-amino-7- (1H-indole-5-yl) -9-isopropyl-8-oxo-8,9-dihydro-7H-purin-2-yl] amino} -3- Fluoro-N, N-dimethylbenzamide,
(25) 6-Amino-9-Cyclopentyl-7- (3-Hydroxyphenyl) -2-({4- [2- (1-pyrrolidinyl) ethyl] phenyl} amino) -7,9-dihydro-8H-purine -8-on,
(26) 4-{[6-amino-9-cyclopentyl-7- (3-hydroxyphenyl) -8-oxo-8,9-dihydro-7H-purin-2-yl] amino} -3-methoxy-N , N-dimethylbenzamide,
(27) 4-{[6-amino-7- (4-chloro-3-hydroxyphenyl) -9-isopropyl-8-oxo-8,9-dihydro-7H-purin-2-yl] amino} -N -[2- (Dimethylamino) ethyl] -3-fluorobenzamide,
(28) 6-Amino-9-Cyclopentyl-2-{[2-fluoro-4- (4-morpholinylcarbonyl) phenyl] amino} -7- (3-hydroxyphenyl) -7,9-dihydro-8H -Prince-8-on,
(29) 4-{[6-amino-9-cyclopentyl-7- (3-hydroxyphenyl) -8-oxo-8,9-dihydro-7H-purin-2-yl] amino} benzamide,
(30) 6-Amino-9-Cyclopentyl-7- (3-Hydroxyphenyl) -2-{[4- (4-morpholinyl) phenyl] amino} -7,9-dihydro-8H-purine-8-one,
(31) 4-{[6-Amino-9-Cyclopentyl-7- (3-Hydroxyphenyl) -8-oxo-8,9-dihydro-7H-purin-2-yl] amino} -3-fluoro-N -(2-Hydroxyethyl) benzamide,
(32) 6-Amino-2- ({2-fluoro-4-[(4-hydroxy-1-piperidinyl) carbonyl] phenyl} amino) -7- (1H-indole-5-yl) -9- (Tetrahydro-3-furanyl) -7,9-dihydro-8H-purine-8-on,
(33) 5-{[6-amino-7- (1H-indole-5-yl) -9-isopropyl-8-oxo-8,9-dihydro-7H-purin-2-yl] amino} -N, N-dimethyl-2-pyridinecarboxamide,
(34) 6-Amino-7- (1H-indole-5-yl) -9-isopropyl-2-[(2-methyl-4-oxo-4H-chromen-7-yl) amino] -7,9- Dihydro-8H-purine-8-on,
(35) 6-Amino-7- (1H-indole-5-yl) -9-isopropyl-2-[(1-oxo-1,3-dihydro-2-benzofuran-5-yl) amino] -7, 9-Dihydro-8H-Purin-8-on,
(36) 7-{[6-amino-7- (1H-indole-5-yl) -9-isopropyl-8-oxo-8,9-dihydro-7H-purin-2-yl] amino} -4- Methyl-2H-1,4-benzoxazine-3 (4H) -one, or (37) 4-{[6-amino-7- (1H-indole-5-yl) -8-oxo-9- (tetrahydro) -3-Flanyl) -8,9-dihydro-7H-purin-2-yl] amino} -3-fluorobenzenesulfonamide according to claim 1, a salt thereof, an N-oxide compound thereof, or a solvent thereof. Japanese product. A pharmaceutical composition comprising the compound represented by the general formula (I) according to claim 1, a salt thereof, an N-oxide compound thereof, or a solvate thereof as an active ingredient. The composition according to claim 9, which is a Brk inhibitor. A preventive and / or therapeutic agent for Brk-related diseases containing the compound represented by the general formula (I) according to claim 1, a salt thereof, an N-oxide form thereof, or a solvate thereof as an active ingredient. The therapeutic agent according to claim 11, wherein the Brk-related disease is cancer. Cancers include breast cancer, ovarian cancer, colon cancer, lung cancer, prostate cancer, head and neck cancer, lymphoma, brain tumor, glioma, pituitary adenomas, vine malignant melanoma, meningeal tumor, thoracic adenomas, Nakaderma, esophageal cancer, gastric cancer, duodenal cancer, hepatocellular carcinoma, bile duct cancer, bile duct cancer, pancreatic cancer, renal cell carcinoma, renal pelvis / urinary tract cancer, bladder cancer, penis cancer 12. 10. Therapeutic agent. A compound represented by the general formula (I) according to claim 1, a salt thereof, an N-oxide form thereof, or a solvent mixture thereof, an alkylating agent, an antimetabolite, an anticancer antibiotic, a vegetable preparation, and the like. Hormonal agents, platinum compounds, immunomodulators, topoisomerase inhibitors, biological response regulators, kinase inhibitors, histone deacetylase (HDAC) inhibitors, proteasome inhibitors, anti-CD20 antibodies, anti-HER2 antibodies, anti-EGFR A drug in combination with at least one selected from an antibody and an anti-VEGF antibody. A compound represented by the general formula (I) according to claim 1, a salt thereof, an N-oxide form thereof, or a solvate thereof for the treatment of cancer. Use of the compound represented by the general formula (I) according to claim 1, a salt thereof, an N-oxide form thereof, or a solvate thereof for producing a therapeutic agent for cancer.